Polycyclic heteroaryl substituted triazoles useful as axl inhibitors

ABSTRACT

Polycyclic heteroaryl substituted triazoles and pharmaceutical compositions containing the compounds are disclosed as being useful in inhibiting the activity of the receptor protein tyrosine kinase Axl. Methods of using the compounds in treating diseases or conditions associated with Axl activity are also disclosed.

FIELD OF THE INVENTION

This invention is directed to polycyclic heteroaryl substitutedtriazoles and pharmaceutical compositions thereof which are useful asinhibitors of the receptor protein tyrosine kinase known as Axl. Thisinvention is also directed to methods of using the compounds andcompositions in treating diseases and conditions associated with Axlactivity, particularly in treating diseases and conditions associatedwith angiogenesis and/or cell proliferation.

BACKGROUND OF THE INVENTION

All of the protein kinases that have been identified to date in thehuman genome share a highly conserved catalytic domain of around 300 aa.This domain folds into a bi-lobed structure in which reside ATP-bindingand catalytic sites. The complexity of protein kinase regulation allowsmany potential mechanisms of inhibition including competition withactivating ligands, modulation of positive and negative regulators,interference with protein dimerization, and allosteric or competitiveinhibition at the substrate or ATP binding sites.

Axl (also known as UFO, ARK, and Tyro7; nucleotide accession numbersNM_(—)021913 and NM_(—)001699; protein accession numbers NP_(—)068713and NP_(—)001690) is a receptor protein tyrosine kinase (RTK) thatcomprises a C-terminal extracellular ligand-binding domain andN-terminal cytoplasmic region containing the catalytic domain. Theextracellular domain of Axl has a unique structure that juxtaposesimmunoglobulin and fibronectin Type III repeats and is reminiscent ofthe structure of neural cell adhesion molecules. Axl and its two closerelatives, Mer/Nyk and Sky (Tyro3/Rse/Dtk), collectively known as theTyro3 family of RTK's, all bind and are stimulated to varying degrees bythe same ligand, Gas6 (growth arrest specific-6), a ˜76 kDa secretedprotein with significant homology to the coagulation cascade regulator,Protein S. In addition to binding to ligands, the Axl extracellulardomain has been shown to undergo homophilic interactions that mediatecell aggregation, suggesting that one important function of Axl may beto mediate cell-cell adhesion.

Axl is predominantly expressed in the vasculature in both endothelialcells (EC's) and vascular smooth muscle cells (VSMC's) and in cells ofthe myeloid lineage and is also detected in breast epithelial cells,chondrocytes, Sertoli cells and neurons. Several functions includingprotection from apoptosis induced by serum starvation, TNF-α or theviral protein E1A, as well as migration and cell differentiation havebeen ascribed to Axl signaling in cell culture. However, Axl−/− miceexhibit no overt developmental phenotype and the physiological functionof Axl in vivo is not clearly established in the literature.

Angiogenesis (the formation of new blood vessels) is limited tofunctions such as wound healing and the female reproductive cycle inhealthy adults. This physiological process has been co-opted by tumors,thus securing an adequate blood supply that feeds tumor growth andfacilitates metastasis. Deregulated angiogenesis also a feature of manyother diseases (for example, psoriasis, rheumatoid arthritis,endometriosis and blindness due to age-related macular degeneration(AMD), retinopathy of prematurity and diabetes) and often contributes tothe progression or pathology of the condition.

The overexpression of Axl and/or its ligand has also been reported in awide variety of solid tumor types including, but not limited to, breast,renal, endometrial, ovarian, thyroid, non-small cell lung carcinoma, anduveal melanoma as well as in myeloid leukemia's. Furthermore, itpossesses transforming activity in NIH3T3 and 32D cells. It has beendemonstrated that loss of Axl expression in tumor cells blocks thegrowth of solid human neoplasms in an in vivo MDA-MB-231 breastcarcinoma xenograft model. Taken together, these data suggest Axlsignaling can independently regulate EC angiogenesis and tumor growthand thus represents a novel target class for tumor therapeuticdevelopment.

The expression of Axl and Gas6 proteins is upregulated in a variety ofother disease states including endometriosis, vascular injury and kidneydisease and Axl signaling is functionally implicated in the latter twoindications. Axl-Gas6 signaling amplifies platelet responses and isimplicated in thrombus formation. Axl may thus potentially represent atherapeutic target for a number of diverse pathological conditionsincluding solid tumors, including, but not limited to, breast, renal,endometrial, ovarian, thyroid, non-small cell lung carcinoma and uvealmelanoma; liquid tumors, including but not limited to, leukemias(particularly myeloid leukemias) and lymphomas; endometriosis, vasculardisease/injury (including but not limited to restenosis, atherosclerosisand thrombosis), psoriasis; visual impairment due to maculardegeneration; diabetic retinopathy and retinopathy of prematurity;kidney disease (including but not limited to glomerulonephritis,diabetic nephropathy and renal transplant rejection), rheumatoidarthritis; osteoporosis, osteoarthritis and cataracts.

SUMMARY OF THE INVENTION

This invention is directed to certain polycyclic heteroaryl substitutedtriazoles which are useful as Axl inhibitors, methods of using suchcompounds in treating diseases and conditions associated with Axlactivity and pharmaceutical compositions comprising such compounds.

Accordingly, in one aspect, this invention is directed to compounds offormula (I):

wherein:

-   A is ═C(H)— or ═N—;-   R¹ is —N(R²)R³, —N(R²)C(O)R³ or —N(R²)—R⁴—C(O)OR³;-   or R¹ is an N-heterocyclyl optionally substituted by one or more    substituents selected from the group consisting of halo and    —R⁴—C(O)OR²;-   each R² and R³ is hydrogen, alkyl, alkenyl, optionally substituted    aralkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl and optionally substituted heteroarylalkyl; and-   each R⁴ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain;-   as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof;-   provided that the compound of formula (I) is not a compound selected    from the group consisting of:-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((bicyclo[2.2.1]heptan-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((bicyclo[2.2.1]heptan-2-yl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-diethylamino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.

In another aspect, this invention is directed to compounds of formula(II):

wherein:

-   R⁵ is N-heterocyclyl optionally substituted by N-heterocyclyl; and-   R⁶ is halo;-   as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

In another aspect, this invention is directed to pharmaceuticalcompositions comprising a pharmaceutically acceptable excipient and acompound of formula (I), as described above, as an isolated stereoisomeror mixture thereof, or a pharmaceutically acceptable salt thereof, or acompound of formula (II), as described above, as an isolatedstereoisomer or mixture thereof, or a pharmaceutically acceptable saltthereof.

In another aspect, this invention is directed to methods of treating adisease or condition associated with Axl activity in a mammal, whereinthe methods comprise administering to the mammal a therapeuticallyeffective amount of a compound of formula (I), as described above, as anisolated stereoisomer or mixture thereof, or a pharmaceuticallyacceptable salt thereof, or a therapeutically effective amount of apharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of formula (I), as described above, as anisolated stereoisomer or mixture thereof, or a pharmaceuticallyacceptable salt thereof, or a compound of formula (II), as describedabove, as an isolated stereoisomer or mixture thereof, or apharmaceutically acceptable salt thereof, or a therapeutically effectiveamount of a pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of formula (II), as described above,as an isolated stereoisomer or mixture thereof, or a pharmaceuticallyacceptable salt thereof.

In another aspect, this invention provides methods of preparing an(S)-enantiomer of the following formula:

where n and m are the same and are 0, 1 or 2;

-   R⁷ is nitro, halo or —C(O)OR²; and-   R² is hydrogen, alkyl, alkenyl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl and optionally substituted heteroaryl;    wherein the method comprises treating a compound of formula (I):

where n and m are the same and are 0, 1 or 2;

-   R⁷ is nitro, halo or —C(O)OR²; and-   R² is hydrogen, alkyl, alkenyl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl and optionally substituted heteroaryl;    with an amino donor molecule in the presence of a catalytic amount    of a (S)-specific transaminase under suitable conditions to form the    (S)-enantiomer.

In another aspect, this invention provides assays to determine acompound of the invention effectiveness in inhibiting Axl activity in acell-based assay.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

“Amino” refers to the —NH₂ radical.

“Carboxy” refers to the —C(O)OH radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to twelve carbon atoms, preferably one toeight carbon atoms or one to six carbon atoms (“lower alkyl”), and whichis attached to the rest of the molecule by a single bond, for example,methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing at least onedouble bond, having from two to twelve carbon atoms, preferably one toeight carbon atoms and which is attached to the rest of the molecule bya single bond, for example, ethenyl, prop-1-enyl, but-1-enyl,pent-1-enyl, penta-1,4-dienyl, and the like.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through one carbon in the alkylene chain or through any two carbonswithin the chain.

“Amino-donor molecule” refers to a organic molecule comprising a primaryamine (—NH₂) group and which is suitable for the processes disclosedherein. Examples of amino-donor molecules include, but are not limitedto, α-amino acids, such as alanine and phenylalanine, isopropylamine,1-ethylpropylamine, 1,1,3,3-tetramethylbutylamine,1,2-dimethylbutylamine, sec-butylamine, 1-phenylethylamine and the like.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 14 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical may be a monocyclic, bicyclic, ortricyclic system and which may include spiro ring systems. An arylradical is commonly, but not necessarily, attached to the parentmolecule via an aromatic ring of the aryl radical.

“Aralkyl” refers to a radical of the formula —R_(b)—R_(c) where R_(b) isan alkylene chain as defined above and R_(c) is one or more arylradicals as defined above, for example, benzyl, diphenylmethyl and thelike.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include spiro or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms,more preferably from five to seven carbons and which is saturated orunsaturated and attached to the rest of the molecule by a single bond.For purposes of this invention, a bridged ring system is a systemwherein two non-adjacent ring atoms thereof are connected through anatom or a group of atoms. Monocyclic cycloalkyl radicals includenon-bridged cycloalkyl radicals, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclicradicals include fused, spiro or bridged cycloalkyl radicals, forexample, C₁₀ radicals such as adamantanyl (bridged) and decalinyl(fused), and C₇ radicals such as bicyclo[3.2.0]heptanyl (fused),norbornanyl and norbornenyl (bridged), as well as substituted polycyclicradicals, for example, substituted C₇ radicals such asbicyclo[2.2.1]heptenyl (bridged) and 7,7-dimethylbicyclo[2.2.1]heptanyl(bridged), and the like.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)R_(g) whereR_(b) is an alkylene chain as defined above and R_(g) is a cycloalkylradical as defined above.

“Enantiomeric excess” or “ee” refers to a product wherein one enantiomeris present in excess of the other, and is defined as the absolutedifference in the mole fraction of each enantiomer. Enantiomeric excessis typically expressed as a percentage of an enantiomer present in amixture relative to the other enantiomer. For purpose of this invention,the (S)-enantiomer of the invention is considered to be substantiallyfree of the (R)-enantiomer when the (S)-enantiomer is present inenantiomeric excess of greater than 80%, preferably greater than 90%,more preferably greater than 95% and most preferably greater than 99%.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, for example,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical which comprises one to twelve carbon atoms and from one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur. Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include spiro or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be partially or fullysaturated. Examples of such heterocyclyl radicals include, but are notlimited to, dioxolanyl, 1,4-diazepanyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl,octahydro-1H-pyrrolo[3,2-c]pyridinyl,octahydro-1H-pyrrolo[2,3-c]pyridinyl,octahydro-1H-pyrrolo[2,3-b]pyridinyl,octahydro-1H-pyrrolo[3,4-b]pyridinyl, octahydropyrrolo[3,4-c]pyrrolyl,octahydro-1H-pyrido[1,2-a]pyrazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl,4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuranyl, thienyl[1,3]dithianyl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, azetidinyl,octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl,decahydroprazino[1,2-a]azepinyl, azepanyl, azabicyclo[3.2.1]octyl, and2,7-diazaspiro[4.4]nonanyl.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl radical to the rest of the molecule is through anitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical maybe optionally substituted as described above for heterocyclyl radicals.

Heteroaryl” refers to a 5- to 14-membered ring system radical comprisinghydrogen atoms, one to thirteen carbon atoms, one to six heteroatomsselected from the group consisting of nitrogen, oxygen and sulfur, andat least one aromatic ring. A heteroaryl radical is commonly, but notnecessarily, attached to the parent molecule via an aromatic ring of theheteroaryl radical. For purposes of this invention, the heteroarylradical may be a monocyclic, bicyclic or tricyclic ring system, whichmay include spiro ring systems; and the nitrogen, carbon or sulfur atomsin the heteroaryl radical may be optionally oxidized; the nitrogen atommay be optionally quaternized. For purposes of this invention, thearomatic ring of the heteroaryl radical need not contain a heteroatom,as long as one ring of the heteroaryl radical contains a heteroatom. Forexample, 1,2,3,4-tetrahydroisoquinolin-7-yl is considered a “heteroaryl”for the purposes of this invention. Except for the polycyclicheteroaryls containing more than 14 ring atoms, as described above inthe Summary of the Invention, a “heteroaryl” radical as defined hereincan not contain rings having more than 7 members and cannot containrings wherein two non-adjacent members thereof are connected through anatom or a group of atoms (i.e., a bridged ring system). Examples ofheteroaryl radicals include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-c]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,1,2,3,4,5,6-hexahydrobenzo[d]azocin-8-yl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl, 2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl,3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl,6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridinyl,6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-c]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-c]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, 1,2,3,4-tetrahydroisoquinolin-7-yl, triazinyl,thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl,thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl).

“Keto acid” refers to a carboxylic acid additionally containing a ketonefunctional group. An “2-keto acid” refers to a carboxylic acid whereinthe ketone functional group is adjacent to the carboxylic acid (—C(O)OH)group.

Certain chemical groups named herein may be preceded by a shorthandnotation indicating the total number of carbon atoms that are to befound in the indicated chemical group. For example; C₇-C₁₂alkyldescribes an alkyl group, as defined below, having a total of 7 to 12carbon atoms, and C₄-C₁₂cycloalkylalkyl describes a cycloalkylalkylgroup, as defined below, having a total of 4 to 12 carbon atoms. Thetotal number of carbons in the shorthand notation does not includecarbons that may exist in substituents of the group described.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and domestic animals, such as cats, dogs,swine, cattle, sheep, goats, horses, rabbits, and the like. Preferably,for purposes of this invention, the mammal is a human.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution. When a functional group is described as “optionallysubstituted,” and in turn, substitutents on the functional group arealso “optionally substituted” and so on, for the purposes of thisinvention, such iterations are limited to five.

“Pharmaceutically acceptable excipient” includes without limitation anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isotonic agent, solvent,or emulsifier which has been approved by the United States Food and DrugAdministration as being acceptable for use in humans or domesticanimals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, benethamine,benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine,triethanolamine, tromethamine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline and caffeine.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, for example,humans. Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Therapeutically effective amount” refers to that amount of a compoundof the invention which, when administered to a mammal, preferably ahuman, is sufficient to effect treatment, as defined below, of a diseaseor condition of interest in the mammal, preferably a human. The amountof a compound of the invention which constitutes a “therapeuticallyeffective amount” will vary depending on the compound, the disease orcondition and its severity, and the age of the mammal to be treated, butcan be determined routinely by one of ordinary skill in the art havingregard to his own knowledge and to this disclosure.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or condition of interest, and includes:

(i) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;

(ii) inhibiting the disease or condition, i.e., arresting itsdevelopment;

(iii) relieving the disease or condition, i.e., causing regression ofthe disease or condition; or

(iv) stabilizing the disease or condition.

“Transaminases” as used herein refers to naturally occurring ornon-natural enzymes which catalyze the transfer of an amino group froman amino donor molecule to a ketone-containing molecule, preferably to acyclic ketone fused to an aromatic ring, to produce an optically activemolecule. Transaminases, or aminotransferases, have highstereoselectivity for a given enantiomer. Thus, the process oftransamination utilizing a transaminase is a chiral synthesis, not aresolution.

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centres and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)-for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, such as HPLC using a chiralcolumn. When the compounds described herein contain olefinic doublebonds or other centres of geometric asymmetry, and unless specifiedotherwise, it is intended that the compounds include both E and Zgeometric isomers. Likewise, all tautomeric forms are also intended tobe included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system wherein thecompounds of the invention are named herein as derivatives of thecentral core structure, i.e., the triazole structure. For complexchemical names employed herein, a substituent group is named before thegroup to which it attaches. For example, cyclopropylethyl comprises anethyl backbone with cyclopropyl substituent. In chemical structurediagrams, all bonds are identified, except for some carbon atoms, whichare assumed to be bonded to sufficient hydrogen atoms to complete thevalency.

For example, a compound of formula (II), as set forth above in theSummary of the Invention, where R⁵ is4-(4-(pyrrolidin-1-yl)piperidin-1-yl) and R⁶ is 3-fluoro is named hereinas1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine.

For purposes of this invention, the depiction of the bond attaching thepolycyclic substituent containing the R³ substituent to the parenttriazole moiety in formula (I), as shown below:

is intended to include only the four regioisomers shown below, i.e.,compounds of formula (I-1), (I-2), (I-3) and (I-4):

Embodiments of the Invention

Of the various aspects of the compounds of the invention, as set forthabove in the Summary of the Invention, certain embodiments arepreferred.

One embodiment of the invention is a compound of formula (I), as setforth above in the Summary of the Invention, as an isolated stereoisomeror mixture thereof, or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is where a compound of formula (I),as set forth above in the Summary of the Invention, is a compound offormula (Ia):

wherein:

-   A is ═C(H)— or ═N—;-   R¹ is —N(R²)R³, —N(R²)C(O)R³ or —N(R²)—R⁴—C(O)OR³;-   or R¹ is an N-heterocyclyl optionally substituted by one or more    substituents selected from the group consisting of halo and    —R⁴—C(O)OR²;-   each R² and R³ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl and optionally substituted heteroarylalkyl; and    -   each R⁴ is independently selected from the group consisting of a        direct bond and an optionally substituted straight or branched        alkylene chain,        as an isolated stereoisomer or mixture thereof, or a        pharmaceutically acceptable salt thereof.

Another embodiment of the invention is where a compound of formula (I),as set forth above in the Summary of the Invention, is a compound offormula (Ia), as set forth above, wherein:

-   A is ═C(H)—;-   R¹ is —N(R²)R³, —N(R²)C(O)R³ or —N(R²)—R⁴—C(O)OR³;-   or R¹ is an N-heterocyclyl optionally substituted by one or more    substituents selected from the group consisting of halo and    —R⁴—C(O)OR²;-   each R² and R³ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl and optionally substituted heteroarylalkyl; and    -   each R⁴ is independently selected from the group consisting of a        direct bond and an optionally substituted straight or branched        alkylene chain,        as an isolated stereoisomer or mixture thereof, or a        pharmaceutically acceptable salt thereof.

Another embodiment of the invention is where a compound of formula (I),as set forth above in the Summary of the Invention, is a compound offormula (Ia), as set forth above, wherein:

-   A is ═C(H)—;-   R¹ is —N(R²)R³; and-   R² and R³ are each independently selected from the group consisting    of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl and optionally substituted heteroarylalkyl,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is where a compound of formula (Ia),as set forth above, is a compound of formula (Ia1)

wherein:

-   R² and R³ are each independently selected from the group consisting    of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl and optionally substituted heteroarylalkyl.

Another embodiment of the invention is a compound of formula (Ia1), asset forth above, wherein R² and R³ are each independently selected fromthe group consisting of hydrogen, alkyl and alkenyl, as an isolatedstereoisomer or mixture thereof, or a pharmaceutically acceptable saltthereof.

Another embodiment of the invention is a compound of formula (Ia1), asset forth above, selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-methylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((propyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-propylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3,3-dimethylbut-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-pentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2,2-dimethylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-methylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-ethylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(but-2-enylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(butyl(but-2-enyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula (Ia1), asset forth above, wherein R² and R³ are each independently selected fromthe group consisting of hydrogen, optionally substituted cycloalkyl andoptionally substituted cycloalkylalkyl, as an isolated stereoisomer ormixture thereof, or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula (Ia1), asset forth above, selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7s)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1    ,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((1-cyclopentylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1    ,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1    ,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula (Ia1), asset forth above, wherein R² and R³ are each independently selected fromthe group consisting of hydrogen, optionally substituted aralkyl andoptionally substituted heteroarylalkyl, as an isolated stereoisomer ormixture thereof, or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula (Ia1), asset forth above, selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((5-chlorothien-2-yl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-carboxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1    ,2,4-triazole-3,5-diamine; and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((3-bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is where a compound of formula (I),as set forth above in the Summary of the Invention, is a compound offormula (Ia), as set forth above, wherein:

-   A is ═C(H)—;-   R¹ is —N(R²)C(O)R³; and-   R² and R³ are each independently selected from the group consisting    of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl and optionally substituted heteroarylalkyl,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is where a compound of formula (Ia),as set forth above, is a compound of formula (Ia2):

-   wherein R² and R³ are each independently selected from the group    consisting of hydrogen and alkyl,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula (Ia2), asset forth above, which is1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(acetamido)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,as an isolated stereoisomer or mixture thereof, or a pharmaceuticallyacceptable salt thereof.

Another embodiment of the invention is where a compound of formula (I),as set forth above in the Summary of the Invention, is a compound offormula (Ia), as set forth above, wherein:

-   A is ═C(H)—;-   R¹ is —N(R²)—R⁴—C(O)OR³;-   R² and R³ are each independently selected from the group consisting    of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl and optionally substituted heteroarylalkyl; and-   R⁴ is selected from the group consisting of a direct bond and an    optionally substituted straight or branched alkylene chain,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is where a compound of formula (Ia),as set forth above, is a compound of formula (Ia3):

wherein:

-   R² and R³ are each independently selected from the group consisting    of hydrogen and alkyl; and-   R⁴ is selected from the group consisting of a direct bond and a    methylene chain,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula (Ia3), asset forth above, selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((carboxymethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is where a compound of formula (I),as set forth above in the Summary of the Invention, is a compound offormula (Ia), as set forth above, wherein:

-   A is ═C(H)—;-   R¹ is an N-heterocyclyl optionally substituted by one or more    substituents selected from the group consisting of halo and    —R⁴—C(O)OR²; and-   R² is selected from the group consisting of hydrogen, alkyl,    alkenyl, optionally substituted aralkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl and optionally    substituted heteroarylalkyl,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is where a compound of formula (I),as set forth above in the Summary of the Invention, is a compound offormula (Ia), as set forth above, wherein:

-   A is ═C(H)—;-   R¹ is pyrrolidinyl, piperidinyl or piperazinyl, each independently    optionally substituted by one or more substituents selected from the    group consisting of halo and —R⁴—C(O)OR²; and-   R² is selected from the group consisting of hydrogen and alkyl,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula (Ia), asset forth above, selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(methoxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4,4-difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is where a compound of formula (I),as set forth above in the Summary of the Invention, is a compound offormula (Ia), as set forth above, wherein:

-   A is ═N—;-   R¹ is —N(R²)R³, —N(R²)C(O)R³ or —N(R²)—R⁴—C(O)OR³;-   or R¹ is an N-heterocyclyl optionally substituted by one or more    substituents selected from the group consisting of halo and    —R⁴—C(O)OR²;-   each R² and R³ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl and optionally substituted heteroarylalkyl; and-   each R⁴ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is where a compound of formula (I),as set forth above in the Summary of the Invention, is a compound offormula (Ia), as set forth above, wherein:

-   A is ═N—;-   R¹ is —N(R²)—R⁴—C(O)OR³,-   each R² and R³ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl and optionally substituted heteroarylalkyl; and-   each R⁴ is independently selected from the group consisting of a    direct bond or an optionally substituted straight or branched    alkylene chain,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is where a compound of formula (Ia),as set forth above, is a compound of formula (Ia4):

wherein:

-   R² and R³ are each independently selected from the group consisting    of hydrogen and alkyl; and-   R⁴ is a direct bond or a methylene chain,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula (Ia3), asset forth above, which is1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,as an isolated stereoisomer or mixture thereof, or a pharmaceuticallyacceptable salt thereof.

Another embodiment of the invention is where a compound of formula (Ia),as set forth above, is a compound of formula (Ia5):

wherein:

-   R² and R³ are each independently selected from the group consisting    of hydrogen, alkyl, cycloalkyl and cycloalkylalkyl,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula (Ia5), asset forth above, selected from the group consisting of:

-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((methylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-butylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is where a compound of formula (I),as set forth above in the Summary of the Invention, is a compound offormula (Ib):

wherein:

-   A is ═C(H)— or ═N—;-   R¹ is —N(R²)R³, —N(R²)C(O)R³ or —N(R²)—R⁴—C(O)OR³;-   or R¹ is an N-heterocyclyl optionally substituted by one or more    substituents selected from the group consisting of halo and    —R⁴—C(O)OR²;-   each R² and R³ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl and optionally substituted heteroarylalkyl; and-   each R⁴ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is where a compound of formula (I),as set forth above in the Summary of the Invention, is a compound offormula (Ib), as set forth above, wherein:

-   A is ═C(H)—;-   R¹ is —N(R²)R³, —N(R²)C(O)R³ or —N(R²)—R⁴—C(O)OR³;-   or R¹ is an N-heterocyclyl optionally substituted by one or more    substituents selected from the group consisting of halo and    —R⁴—C(O)OR²;-   each R² and R³ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl and optionally substituted heteroarylalkyl; and-   each R⁴ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is where a compound of formula (I),as set forth above in the Summary of the Invention, is a compound offormula (Ib), as set forth above, wherein:

-   A is ═C(H)—;-   R¹ is —N(R²)—R⁴—C(O)OR³;-   R² and R³ are each independently selected from the group consisting    of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl and optionally substituted heteroarylalkyl; and-   R⁴ is selected from the group consisting of a direct bond and an    optionally substituted straight or branched alkylene chain,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is where a compound of formula (Ib),as set forth above, is a compound of formula (Ib1):

wherein:

-   R² and R³ are each independently selected from the group consisting    of hydrogen and alkyl; and-   R⁴ is selected from the group consisting of a direct bond and a    methylene chain,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula (Ib1), asset forth above, which is1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,as an isolated stereoisomer or mixture thereof, or a pharmaceuticallyacceptable salt thereof.

Another embodiment of the invention is where a compound of formula (I),as set forth above in the Summary of the Invention, is a compound offormula (Ib), as set forth above, wherein:

-   A is ═C(H)—;-   R¹ is an N-heterocyclyl optionally substituted by one or more    substituents selected from the group consisting of halo and    —R⁴—C(O)OR²; and-   R² is selected from the group consisting of hydrogen, alkyl,    alkenyl, optionally substituted aralkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl and optionally    substituted heteroarylalkyl,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is where a compound of formula (I),as set forth above in the Summary of the Invention, is a compound offormula (Ib), as set forth above, wherein:

-   A is ═C(H)—;-   R¹ is pyrrolidinyl optionally substituted by one or more    substituents selected from the group consisting of halo and    —R⁴—C(O)OR²; and-   R² is selected from the group consisting of hydrogen and alkyl,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula (Ib), asset forth above, which is1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine,as an isolated stereoisomer or mixture thereof, or a pharmaceuticallyacceptable salt thereof.

Another embodiment of the invention is a compound of formula (II), asset forth above in the Summary of the Invention, as an isolatedstereoisomer or mixture thereof, or a pharmaceutically acceptable saltthereof.

Another embodiment of the invention is a compound of formula (II), asset forth above in the Summary of the Invention, wherein:

-   R⁵ is piperidinyl substituted by pyrrolidinyl; and-   R⁶ is halo,    as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Another embodiment of the invention is a compound of formula (II), asset forth above in the Summary of the Invention, which is1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine,as an isolated stereoisomer or mixture thereof, or a pharmaceuticallyacceptable salt thereof.

Another embodiment of the invention is a method of preparing an(S)-enantiomer of the following formula:

as set forth above in the Summary of the Invention.

Another embodiment of the invention is a method of preparing an(S)-enantiomer of the following formula:

as set forth above in the Summary of the Invention, wherein the compoundof formula (I) is a compound of formula (Cb-1):

Another embodiment of the invention is a method of preparing an(S)-enantiomer of the following formula:

as set forth above in the Summary of the Invention, wherein the(S)-enantiomer is a compound of formula (Cb-2):

Another embodiment of the invention is a method of preparing an(S)-enantiomer of the following formula:

as set forth above in the Summary of the Invention, wherein the(S)-enantiomer is formed in greater than 80% ee.

Of the various aspects of the pharmaceutical compositions of theinvention comprising a pharmaceutically acceptable excipient and acompound of the invention, as set forth above in the Summary of theInvention, certain embodiments are preferred.

One embodiment of these pharmaceutical compositions is wherein thecompound of the invention therein is selected from any one embodiment ofthe compounds of the invention, as set forth above, or from anycombination of embodiments of the compounds of the invention, as setforth above.

Of the various aspects of methods of treating a disease or conditionassociated with Axl activity in a mammal, wherein the method comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of a compound the invention, certain embodiments are preferred.

One embodiment of these methods is the method wherein the disease orcondition is selected from the group consisting of rheumatoid arthritis,vascular disease, vascular injury, psoriasis, visual impairment due tomacular degeneration, diabetic retinopathy, retinopathy of prematurity,kidney disease, osteoarthritis and cataracts.

One embodiment of these methods is the method wherein a manifestation ofthe disease or condition is solid tumor formation in said mammal.

One embodiment of these methods is the method wherein the disease orcondition is selected from the group consisting of breast carcinoma,renal carcinoma, endometrial carcinoma, ovarian carcinoma, thyroidcarcinoma, non-small cell lung carcinoma, and uveal melanoma.

One embodiment of these methods is the method wherein a manifestation ofthe disease or condition is liquid tumor formation in said mammal.

One embodiment of these methods is the method wherein the disease orcondition is myeloid leukemia or lymphoma.

One embodiment of these methods is the method wherein the disease orcondition is endometriosis.

One embodiment of these methods is the method wherein the disease orcondition is metastasis to the liver.

One embodiment of these methods is the method wherein the compounds ofinvention utilized therein is selected from any one embodiment of thecompounds of the invention, as set forth above, or from any combinationof embodiments of the compounds of the invention, as set forth above.

Another embodiment of the invention are those methods of treating adisease or condition associated with Axl activity by administering tothe mammal a therapeutically effective amount of a pharmaceuticalcomposition of the invention, as set forth above in the Summary of theInvention, wherein the disease or condition is selected from the groupconsisting of rheumatoid arthritis, vascular disease/injury (includingbut not limited to restenosis, atherosclerosis and thrombosis),psoriasis, visual impairment due to macular degeneration, diabeticretinopathy or retinopathy of prematurity, kidney disease (including butnot limited to glomerulonephritis, diabetic nephropathy and renaltransplant rejection), osteoarthritis and cataracts.

Another embodiment of the invention are those methods of treating adisease or condition associated with Axl activity by administering tothe mammal a therapeutically effective amount of a pharmaceuticalcomposition of the invention, as set forth above in the Summary of theInvention, wherein the disease or condition is selected from the groupconsisting of breast carcinoma, renal carcinoma, endometrial carcinoma,ovarian carcinoma, thyroid carcinoma, non-small cell lung carcinoma,uveal melanoma, myeloid leukemia and lymphoma.

Another embodiment of the invention are those methods of treating adisease or condition associated with Axl activity by administering tothe mammal of therapeutically effective amount of a pharmaceuticalcomposition of the invention, as set forth above in the Summary of theInvention, wherein the disease or condition is endometriosis.

Specific embodiments of the invention are described in more detail inthe following sections.

Utility and Testing of the Compounds of the Invention

The oncogenic RTK, Axl, was recently identified, using aretroviral-based functional genetic screening protocol, as a regulatorof haptotactic migration, which is a key event in angiogenesis. Axlinhibition by RNAi-mediated silencing blocked endothelial cellmigration, proliferation and in vitro tube formation. Theseobservations, which were disclosed at the American Association CancerResearch General Meeting, Apr. 16-20, 2005, Anaheim, Calif., and The 7thAnnual Symposium on Anti-Angiogenic Agents, Feb. 10-13, 2005, San Diego,Calif.; (Requirement for The Receptor Tyrosine Kinase Axl inAngiogenesis and Tumor Growth, Holland, S. J. Powell, M. J., Franci, C.,Chan, E., Friera, A.M., Atchison, R., Xu, W., McLaughlin, J., Swift, S.E., Pali, E., Yam, G., Wong, S., Xu, X., Hu, Y., Lasaga, J., Shen, M.,Yu, S., Daniel, R., Hitoshi, Y., Bogenberger, J., Nor, J. E., Payan, D.G and Lorens, J. B), were substantiated by an in vivo study whichdemonstrated that stable, shRNAi-mediated Axl knockdown impairedformation of functional human blood vessels in a mouse model of humanangiogenesis. These observations were published in a peer reviewedjournal (Holland S J, Powell M J, Franci C, Chan E W, Friera A M,Atchison R E, McLaughlin J, Swift S E, Pali E S, Yam G, Wong S, LasagaJ, Shen M R, Yu S, Xu W, Hitoshi Y, Bogenberger J, Nor J E, Payan D G,Lorens J B. “Multiple roles for the receptor tyrosine kinase axl intumor formation.” Cancer Res. (2005) Vol 65 pp 9294-303. Theseobservations are also disclosed in U.S. Published Patent Application2005/0118604 and European Patent Application 1 563 094, the disclosuresof which are incorporated in full by reference. Axl signaling,therefore, impacts multiple functions required for neovascularization invitro, and regulates angiogenesis in vivo. Regulation of thesepro-angiogenic processes required the catalytic activity of Axl. Thus,Axl-mediated angiogenic stimulation would be amenable to modulation by asmall molecule inhibitor of Axl catalytic activity.

Accordingly, the compounds of the invention are small moleculeinhibtiors of Axl catalytic activity, and are therefore useful intreating diseases and conditions which are associated with Axl catalyticactivity including those diseases and conditions which are characterizedby angiogenesis and/or cell proliferation. In particular, the compoundsof the invention and pharmaceutical compositions of the invention areuseful in treating diseases and conditions which are alleviated by themodulation of Axl activity. For purposes of this invention, diseases andconditions which are alleviated by the “modulation of Axl activity”includes diseases and conditions which are alleviated by a decrease inAxl activity and diseases and conditions which are alleviated by anincrease in Axl activity. Preferably such diseases and conditions arealleviated by a decrease in Axl activity. Diseases and conditions whichare alleviated by the modulation of Axl activity include, but are notlimited to, solid tumors, including, but not limited to, breast, renal,endometrial, ovarian, thyroid, and non-small cell lung carcinoma,melanoma, prostate carcinoma, sarcoma, gastric cancer and uvealmelanoma; liquid tumors, including but not limited to, leukemias(particularly myeloid leukemias) and lymphomas; endometriosis, vasculardisease/injury (including but not limited to restenosis, atherosclerosisand thrombosis), psoriasis; visual impairment due to maculardegeneration; diabetic retinopathy and retinopathy of prematurity;kidney disease (including but not limited to glomerulonephritis,diabetic nephropathy and renal transplant rejection), rheumatoidarthritis; osteoarthritis, osteoporosis and cataracts.

In addition to the foregoing, the compounds of the invention are usefulin treating diseases and conditions which are affected by the followingbiological processes: Invasion, migration, metastasis, or drugresistance as manifested in cancer; stem cell biology as manifested incancer; invasion, migration, adhesion, or angiogenesis as manifested inendometriosis; vascular remodeling as manifested in cardiovasculardisease, hypertension or vascular injury; bone homeostatasis asmanifested in osteoporosis or osteoarthritis; viral infection asmanifested, for example, in ebola virus infection; or differentiation asmanifested in obesity. The compounds of the invention may also be usedto modulate inflammatory processes by treating sepsis, acting as vaccineadjuvants, and/or potentiating the immune response in immuno-compromisedpatients.

In one embodiment, the compounds of the invention are effective intreating metastasis to the liver. For example, treatment with compoundsof the invention can result in pronounced reduction in the developmentof liver micrometastases. One method of the invention is treatment of apatient with compounds of the invention to reduce metastasis to theliver. This method can be done with compounds of the invention alone orin combination with other agents to produce the desired therapeuticbenefit.

The compounds of the invention are also useful in treating cellproliferative disorders. A cell proliferative disorder refers to adisorder characterized by abnormal proliferation of cells. Aproliferative disorder does not imply any limitation with respect to therate of cell growth, but merely indicates loss of normal controls thataffect growth and cell division. Thus, in some embodiments, cells of aproliferative disorder can have the same cell division rates as normalcells but do not respond to signals that limit such growth. Within theambit of “cell proliferative disorder” is neoplasm or tumor, which is anabnormal growth of tissue. Cancer refers to any of various malignantneoplasms characterized by the proliferation of cells that have thecapability to invade surrounding tissue and/or metastasize to newcolonization sites.

Generally, cell proliferative disorders treatable with the compounds ofthe invention relate to any disorder characterized by aberrant cellproliferation. These include various tumors and cancers, benign ormalignant, metastatic or non-metastatic. Specific properties of cancers,such as tissue invasiveness or metastasis, can be targeted using themethods described herein. Cell proliferative disorders include a varietyof cancers, including, among others, breast cancer, ovarian cancer,renal cancer, gastrointestinal cancer, kidney cancer, bladder cancer,pancreatic cancer, lung squamous carcinoma, and adenocarcinoma.

Therefore, in addition to the foregoing, the compounds of the inventionare useful in treating renal cell carcinoma, clear cell carcinoma ofkidney, and renal cell adenocarcinoma; invasive ductal carcinoma,invasive lobular carcinoma, ductal carcinoma, lobular carcinoma in situ,and metastatic breast cancer; basal cell carcinoma, squamous cellcarcinoma, malignant melanoma, and Karposi's sarcoma; small cell andnon-small cell lung carcinoma, bronchial adema, pleuropulmonaryblastoma, and malignant mesothelioma; brain stem and hyptothalamicglioma, cerebellar and cerebral astrocytoma, medullablastoma, ependymaltumors, oligodendroglial, meningiomas, and neuroectodermal and pinealtumors; prostate cancer, testicular cancer, and penile cancer; uterinecancer (endometrial), cervical, ovarian, vaginal, vulval cancers,uterine sarcoma, ovarian germ cell tumor; anal, colon, colorectal,esophageal, gallbladder, stomach (gastric), pancreatic cancer,pancreatic cancer-Islet cell, rectal, small-intestine, and salivarygland cancers; hepatocellular carcinoma, cholangiocarcinoma, mixedhepatocellular cholangiocarcinoma, and primary liver cancer; intraocularmelanoma, retinoblastoma, and rhabdomyosarcoma; laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancers, and lip and oralcancer; squamous neck cancer; metastatic paranasal sinus cancer; B celland C cell lymphomas, non-Hodgkins lymphoma, cutaneous T cell lymphoma,Hodgkins disease, and lymphoma of the central nervous system; acutemyelogenous (myeloid) leukemia, acute lymphoblastic leukemia, chroniclymphocytic leukemia, chronic myelogenous leukemia, and hairy cellleukemia; thyroid cancer, thymoma, and malignant thymoma; bladdercancer; and sarcoma of the soft tissue, osteosarcoma, malignant fibroushistiocytoma, lymphosarcoma, and rhabdomyosarcoma.

Of the B cell lymphoma group of diseases and conditions, the compoundsof the invention are useful in treating precursor B-lymphoblasticleukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia),B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma, B-cellprolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginalzone B-cell lymphoma, hairy cell leukemia, plasma cellmyeloma/plasmacytoma, extranodal marginal zone B-cell lymphoma of MALTtype, nodal marginal zone B-cell lymphoma, follicular lymphoma,mantle-cell lymphoma, diffuse large B-cell lymphoma, mediastinal largeB-cell lymphoma, primary effusion lymphoma, and Burkitt'slymphoma/Burkitt cell leukemia

Of the T cell lymphoma group of diseases and conditions, the compoundsof the invention are useful in treating precursor T-lymphoblasticlymphoma/leukemia (precursor T-cell acute lymphoblastic leukemia),T-cell prolymphocytic leukemia T-cell granular lymphocytic leukemia,aggressive NK-cell leukemia, adult T-cell lymphoma/leukemia (HTLV-1),extranodal NK/T-cell lymphoma, nasal type, enteropathy-type T-celllymphoma, hepatosplenic gamma-delta T-cell lymphoma, subcutaneouspanniculitis-like T-cell lymphoma, mycosis fungoides/Sezary syndrome,anaplastic large-cell lymphoma, T/null cell, primary cutaneous type,peripheral T-cell lymphoma not otherwise characterized,angioimmunoblastic T-cell lymphoma, anaplastic large-cell lymphoma,T/null cell, primary systemic type.

Of the Hodgkins disease group, the compounds of the invention are usefulin treating nodular lymphocyte-predominant Hodgkin's lymphoma, nodularsclerosis Hodgkin's lymphoma (grades 1 and 2), lymphocyte-rich classicalHodgkin's lymphoma, mixed cellularity Hodgkin's lymphoma, and lymphocytedepletion Hodgkin's lymphoma.

The compounds of the invention are also useful in treating myelogenousleukemia (e.g., Philadelphia chromosome positive (t(9;22)(qq34;q11)),chronic neutrophilic leukemia, chronic eosinophilicleukemia/hypereosinophilic syndrome, chronic idiopathic myelofibrosis,polycythemia vera, and essential thrombocythemia, chronic myelomonocyticleukemia, atypical chronic myelogenous leukemia, and juvenilemyelomonocytic leukemia, refractory anemia (with ringed sideroblasts andwithout ringed sideroblasts), refractory cytopenia (myelodysplasticsyndrome) with multilineage dysplasia, refractory anemia(myelodysplastic syndrome) with excess blasts, 5q-syndrome, andmyelodysplastic syndrome with t(9;12)(q22;p12).

The compounds of the invention are also useful in treating acutemyelogenous leukemia with t(8;21)(q22;q22), AML1(CBF-alpha)/ETO, acutepromyelocytic leukemia (AML with t(15;17)(q22;q11-12) and variants,PML/RAR-alpha), acute myelogenous leukemia with abnormal bone marroweosinophils (inv(16)(p13q22) or t(16;16)(p13;q11), CBFb/MYH11X), andacute myelogenous leukemia with 11q23 (MLL) abnormalities, acutemyelogenous leukemia minimally differentiated, acute myelogenousleukemia without maturation, acute myelogenous leukemia with maturation,acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroidleukemia, acute megakaryocytic leukemia, acute basophilic leukemia, andacute panmyelosis with myelofibrosis.

The following animal models provide guidance to one of ordinary skill inthe art in testing the compounds of the invention for their use intreating the disease or condition indicated.

The compounds of the invention may be tested for their use in treatingleukemias and lymphomas by testing the compounds in the xenograft inSCID mouse model using human Axl-expressing cancer cell lines including,but not limited to, HeLa, MDA-MB-231, SK-OV-3, OVCAR-8, DU145, H1299,ACHN, A498 and Caki-1.

The compounds of the invention may be tested for their use in treatingleukemias in the xenograft in SCID or nu/nu mouse model using humanAxl-expressing AML and CML leukemia cell lines.

The compounds of the invention may be tested for their use in treatingendometriosis by using the syngenic mouse model of endometriosis (seeSomigliana, E. et al., “Endometrial ability to implant in ectopic sitescan be prevented by interleukin-12 in a murine model of endometriosis”,Hum. Reprod. (1999), Vol. 14, NO. 12, pp. 2944-50). The compounds mayalso be tested for their use in treating endometriosis by using the ratmodel of endometriosis (see Lebovic, D. I. et al., “Peroxisomeproliferator-activated receptor-gamma induces regression of endometrialexplants in a rat model of endometriosis”, Fertil. Steril. (2004), 82Suppl 3, pp. 1008-13).

The compounds of the invention may be tested for their use in treatingrestenosis by using the balloon-injured rate carotid artery model (seeKim, D. W. et al., “Novel oral formulation of paclitaxel inhibitsneointimal hyperplasia in a rat carotid artery injury model”,Circulation (2004), Vol. 109, No. 12, pp. 1558-63, Epub 2004 Mar. 8).

The compounds of the invention may also be tested for their use intreating restenosis by using the percutaneous transluminal coronaryangioplasty in apoE deficient mouse model (see von der Thusen, J. H. etal., “Adenoviral transfer of endothelial nitric oxide synthaseattenuates lesion formation in a novel murine model of postangioplastyrestenosis”, Arterioscler. Thromb. Vasc. Biol. (2004), Vol. 24, No. 2,pp. 357-62).

The compounds of the invention may be tested for their use in treatingatherosclerosis/thrombosis in the ApoE deficient mouse model (seeNakashima, Y. et al., “ApoE-deficient mice develop lesions of all phasesof atherosclerosis throughout the arterial tree”, Arterioscler. Thromb.(1994), Vol. 14, No. 1, pp. 133-40).

The compounds of the invention may also be tested for their use intreating thrombosis using the collagen-epinephrin-induced pulmonarythromboembolism model and the stasis induced venous thrombosis model(see Angelillo-Scherrer A. et al., “Role of Gas6 receptors in plateletsignaling during thrombus stabilization and implications forantithrombotic therapy”, J Clin Invest. (2005) Vol 115 pp 237-46).

The compounds of the invention may be tested for their use in treatingpsoriasis by using the SCID mouse model or the human skin model ofpsoriasis (see Nickoloff, B. J. et al., “Severe combinedimmunodeficiency mouse and human psoriatic skin chimeras. Validation ofa new animal model”, Am. J. Pathol. (1995), Vol. 146, No. 3, pp. 580-8).

The compounds of the invention may be tested for their use in treatingage-related macular degeneration or diabetic retinopathy by using therat corneal angiogenesis model (see Sarayba M A, Li L, Tungsiripat T,Liu N H, Sweet P M, Patel A J, Osann K E, Chittiboyina A, Benson S C,Pershadsingh H A, Chuck R S. Inhibition of corneal neovascularization bya peroxisome proliferator-activated receptor-gamma ligand. Exp Eye Res.2005 March; 80(3):435-42) or the laser-induced mouse choroidalneovasculation model (see Bora, P. S., et al., “Immunotherapy forchoroidal neovascularization in a laser-induced mouse model simulatingexudative (wet) macular degeneration”, Proc. Natl. Acad. Sci. U.S.A.(2003), Vol. 100, No. 5, pp. 2679-84, Epub 2003 Feb. 14).

The compounds of the invention may be tested for their use in treatingretinopathy of prematurity in the mouse retinopathy of prematurity model(see Smith, L. E. et al., “Oxygen-induced retinopathy in the mouse”,Invest. Ophthalmol. Vis. Sci. (1994), Vol. 35, No. 1, pp. 101-11).

The compounds of the invention may be tested for their use in treatingglomerulonephritis or diabetic nephropathy in the ratanti-Thy1.1-induced experimental mesengial proliferativeglomerulonephritis model (see Smith, L. E. et al. cited above).

The compounds of the invention may be tested for their use in treatingrenal tranplant rejection by using a rat model of chronic renaltransplant rejection (see Yin, J. L. et al., “Expression of growtharrest-specific gene 6 and its receptors in a rat model of chronic renaltransplant rejection”, Transplantation (2002), Vol. 73, No. 4, pp.657-60).

The compounds of the invention may be tested for their use in treatingrheumatoid arthritis by using the CAIA mouse model (see Phadke, K. etal., “Evaluation of the effects of various anti-arthritic drugs on typeII collagen-induced mouse arthritis model”, Immunopharmacology (1985)Vol. 10, No. 1, pp. 51-60).

The compounds of the invention may be tested for their use in treatingosteoarthritis by using the STR/ORT mouse model (see Brewster, M. etal., “Ro 32-3555, an orally active collagenase selective inhibitor,prevents structural damage in the STR/ORT mouse model ofosteoarthritis”, Arthritis. Rheum. (1998), Vol. 41, No. 9, pp. 1639-44).

The compounds of the invention may be tested for their use in treatingosteoporosis by using the ovariectomized rat model (see Wronski, T. J.et al., “Endocrine and pharmacological suppressors of bone turnoverprotect against osteopenia in ovariectomized rats”, Endocrinology(1989), Vol. 125, no. 2, pp 810-6) or the ovariectomized mouse model(see Alexander, J. M. et al., “Human parathyroid hormone 1-34 reversesbone loss in ovariectomized mice”, J Bone Miner Res. (2001), Vol. 16,no. 9, pp 1665-73; Fujioka, M. et al., “Equol, a metabolite of daidzein,inhibits bone loss in ovariectomized mice”, J Nutr. (2004), Vol. 134,no. 10, pp 2623-7).

The compounds of the invention may be tested for their use in treatingcataracts by using the H₂O₂-induced model (see Kadoya, K. et al., “Roleof calpain in hydrogen peroxide induced cataract”, Curr. Eye Res.(1993), Vol. 12, No. 4, pp. 341-6) or the Emory mouse model (see Sheets,N. L. et al., “Cataract- and lens-specific upregulation of ARK receptortyrosine kinase in Emory mouse cataract”, Invest. Ophthalmol. Vis. Sci.(2002), Vol. 43, No. 6, pp. 1870-5).

Pharmaceutical Compositions of the Invention and Administration

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration of agents for serving similar utilities. Thepharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, buccal, rectal, vaginal, andintranasal. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. Pharmaceutical compositions of the invention areformulated so as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy andScience, 2000). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease or condition of interest in accordance with the teachingsof this invention.

A pharmaceutical composition of the invention may be in the form of asolid or liquid. In one aspect, the carrier(s) are particulate, so thatthe compositions are, for example, in tablet or powder form. Thecarrier(s) may be liquid, with the compositions being, for example, anoral oil, injectable liquid or an aerosol, which is useful in, forexample, inhalatory administration.

When intended for oral administration, the pharmaceutical composition ispreferably in either solid or liquid form, where semi-solid,semi-liquid, suspension and gel forms are included within the formsconsidered herein as either solid or liquid.

As a solid composition for oral administration, the pharmaceuticalcomposition may be formulated into a powder, granule, compressed tablet,pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following may be present:binders such as carboxymethylcellulose, ethyl cellulose,microcrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch, lactose or dextrins, disintegrating agents such as alginicacid, sodium alginate, Primogel, corn starch and the like; lubricantssuch as magnesium stearate or Sterotex; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, forexample, a gelatin capsule, it may contain, in addition to materials ofthe above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, forexample, an elixir, syrup, solution, emulsion or suspension. The liquidmay be for oral administration or for delivery by injection, as twoexamples. When intended for oral administration, preferred compositioncontain, in addition to the present compounds, one or more of asweetening agent, preservatives, dye/colorant and flavor enhancer. In acomposition intended to be administered by injection, one or more of asurfactant, preservative, wetting agent, dispersing agent, suspendingagent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for eitherparenteral or oral administration should contain an amount of a compoundof the invention such that a suitable dosage will be obtained.Typically, this amount is at least 0.01% of a compound of the inventionin the composition. When intended for oral administration, this amountmay be varied to be between 0.1 and about 70% of the weight of thecomposition. Preferred oral pharmaceutical compositions contain betweenabout 4% and about 75% of the compound of the invention. Preferredpharmaceutical compositions and preparations according to the presentinvention are prepared so that a parenteral dosage unit contains between0.01 to 10% by weight of the compound prior to dilution of theinvention.

The pharmaceutical composition of the invention may be intended fortopical administration, in which case the carrier may suitably comprisea solution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device. Topical formulations may contain aconcentration of the compound of the invention from about 0.1 to about10% w/v (weight per unit volume).

The pharmaceutical composition of the invention may be intended forrectal administration, in the form, for example, of a suppository, whichwill melt in the rectum and release the drug. The composition for rectaladministration may contain an oleaginous base as a suitablenonirritating excipient. Such bases include, without limitation,lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition of the invention may include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition may include materials that form acoating shell around the active ingredients. The materials that form thecoating shell are typically inert, and may be selected from, forexample, sugar, shellac, and other enteric coating agents.

Alternatively, the active ingredients may be encased in a gelatincapsule.

The pharmaceutical composition of the invention in solid or liquid formmay include an agent that binds to the compound of the invention andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome.

The pharmaceutical composition of the invention may consist of dosageunits that can be administered as an aerosol. The term aerosol is usedto denote a variety of systems ranging from those of colloidal nature tosystems consisting of pressurized packages. Delivery may be by aliquefied or compressed gas or by a suitable pump system that dispensesthe active ingredients. Aerosols of compounds of the invention may bedelivered in single phase, bi-phasic, or tri-phasic systems in order todeliver the active ingredient(s). Delivery of the aerosol includes thenecessary container, activators, valves, subcontainers, and the like,which together may form a kit. One of ordinary skill in the art, withoutundue experimentation may determine preferred aerosols. Thepharmaceutical compositions of the invention may be prepared bymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with sterile,distilled water so as to form a solution. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with the compoundof the invention so as to facilitate dissolution or homogeneoussuspension of the compound in the aqueous delivery system.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy. Generally, atherapeutically effective daily dose is (for a 70 kg mammal) from about0.001 mg/kg (i.e., 0.07 mg) to about 100 mg/kg (i.e., 7.0 gm);preferably a therapeutically effective dose is (for a 70 kg mammal) fromabout 0.01 mg/kg (i.e., 0.7 mg) to about 50 mg/kg (i.e., 3.5 gm); morepreferably a therapeutically effective dose is (for a 70 kg mammal) fromabout 1 mg/kg (i.e., 70 mg) to about 25 mg/kg (i.e., 1.75 gm).

Compounds of the invention, or pharmaceutically acceptable saltsthereof, may also be administered simultaneously with, prior to, orafter administration of one or more other therapeutic agents. Suchcombination therapy includes administration of a single pharmaceuticaldosage formulation which contains a compound of the invention and one ormore additional active agents, as well as administration of the compoundof the invention and each active agent in its own separatepharmaceutical dosage formulation.

For example, a compound of the invention and the other active agent canbe administered to the patient together in a single oral dosagecomposition such as a tablet or capsule, or each agent administered inseparate oral dosage formulations. Where separate dosage formulationsare used, the compounds of the invention and one or more additionalactive agents can be administered at essentially the same time, i.e.,concurrently, or at separately staggered times, i.e., sequentially;combination therapy is understood to include all these regimens.

Preparation of the Compounds of the Invention

The following Reaction Schemes illustrate methods to make compounds ofthis invention, e.g., compounds of formula (I):

where A and R¹ are described above in the Summary of the Invention forcompounds of formula (I), as isolated stereoisomers or mixtures thereof,as tautomers or mixtures thereof, or as pharmaceutically acceptablesalts. In particular, the following Reaction Schemes illustrate methodsto make compounds of formula (I) having the following formula (Ia):

wherein:

-   A is ═C(H)— or ═N—;-   R¹ is —N(R²)R³, —N(R²)C(O)R³, —N(R²)—R⁴—C(O)OR³, or R¹ is an    N-heterocyclyl optionally substituted by one or more substituents    selected from the group consisting of halo and —R⁴—C(O)OR²,-   each R² and R³ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl and optionally substituted heteroaryl; and-   each R⁴ is independently selected from the group consisting of a    direct bond or an optionally substituted straight or branched    alkylene chain; and-   as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

It is understood that one of ordinary skill in the art would be able tomake the compounds of the invention by methods similar to the methodsdescribed herein or by methods known to one of ordinary skill in theart. It is also understood that one of ordinary skill in the art wouldbe able to make in a similar manner as described below other compoundsof formula (I) and the compounds of formula (II), as set forth above inthe Summary of the Invention, not specifically illustrated below byusing the appropriate starting components and modifying the parametersof the synthesis as needed.

It is also understood that in the following Reaction Schemes andthroughout this description, combinations of substituents and/orvariables of the depicted formulae are permissible only if suchcontributions result in stable compounds. It will also be appreciated bythose skilled in the art that in the processes described below thefunctional groups of intermediate compounds may need to be protected bysuitable protecting groups. Such functional groups include hydroxy,amino, mercapto and carboxylic acid. Suitable protecting groups forhydroxy include trialkylsilyl or diarylalkylsilyl (for example,t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl),tetrahydropyranyl, benzyl, and the like. Suitable protecting groups foramino, amidino and guanidino include benzyl, t-butoxycarbonyl,benzyloxycarbonyl, and the like. Suitable protecting groups for mercaptoinclude —C(O)—R″ (where R″ is alkyl, aryl or arylalkyl),p-methoxybenzyl, trityl and the like. Suitable protecting groups forcarboxylic acids include alkyl, aryl or arylalkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are known to one of ordinary skill in the art and asdescribed herein.

The use of protecting groups is described in detail in Green, T. W. andP. G. M. Wuts, Protective Groups in Organic Synthesis (1999), 3rd Ed.,Wiley. As one of skill in the art would appreciate, the protecting groupmay also be a polymer resin such as a Wang resin, Rink resin or a2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of theinvention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”.

In general, starting components may be obtained from sources such asSigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific,TCI, and Fluorochem USA, etc. or synthesized according to sources knownto those skilled in the art (see, for example, Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley,December 2000)) or prepared as described in this invention. ¹H NMRspectra were recorded in CDCl₃, DMSO-d₆, CD₃OD, Acetone-d₆ withtrimethylsilane (TMS) as internal reference using Gemini 300 MHzinstrument. Reagents and solvents were purchased from commercial sourcesand used without further purification. Flash column chromatography wasconducted using silica gel (230-400 mesh) under a positive pressure ofnitrogen. LCMS spectra for purity and mass were recorded using Waters

LCMS instruments. Deionized water was used to dilute the reactions andwash the products. Brine used was prepared by dissolving sodium chlorideinto deionized water to saturation point.

Compounds of formula (Ia), as described above, are generally prepared asillustrated below in Reaction Scheme 1 where A and R¹ are as describedabove for the compounds of formula (Ia) and Ph is a phenyl group:

Compounds of formula (A), formula (B) and formula (D) are commerciallyavailable or can be prepared by methods known to one skilled in the artor by methods disclosed herein.

In general, compounds of formula (Ia) are prepared, as set forth byReaction Scheme 1, by first treating a compound of formula (A) (wherethe phenyl groups therein may be replaced with other suitable groups orsuitably substituted groups known to one skilled in the art) (1.1 equiv)with an equivalent amount of an aniline of formula (B) in an polarsolvent, including, but not limited to, isopropyl alcohol, at ambienttemperatures overnight. The diarylisourea product of formula (C)generally precipitates and isolation can be accomplished via filtration,washing with an appropriate solvent, and drying. Hydrazine hydrate offormula (D) (2 equivalents) is added to a slurry of the compound offormula (C) in an alcohol or other appropriate solvent. Generally, thering formation reaction occurs at ambient temperature and the producttriazole of formula (Ia) can be isolated by standard isolationtechniques. Compounds of formula (Ia) can be subsequently treated withan appropriately substituted alkylating or acylating agent understandard conditions to form compounds of formula (I), as set forth inthe Summary of the Invention, wherein R² and R³ in the compounds soprepared are as described above in the Summary of the Invention forcompounds of formula (I).

Compounds of formula (Ib), which are compounds of formula (I) having thefollowing formula (Ib):

wherein:

-   A is ═C(H)— or ═N—;-   R¹ is —N(R²)R³, —N(R²)C(O)R³, —N(R²)—R⁴—C(O)OR³,-   or R¹ is an N-heterocyclyl optionally substituted by one or more    substituents selected from the group consisting of halo and    —R⁴—C(O)OR²,-   each R² and R³ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl and optionally substituted heteroaryl; and-   each R⁴ is independently selected from the group consisting of a    direct bond or an optionally substituted straight or branched    alkylene chain; and-   as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof;    can be prepared using the synthetic route outlined in Reaction    Scheme 1 in varying amounts depending on the steric and electronic    nature of the starting materials as well as the particular reaction    conditions employed. In some instances, compounds of formula (Ib)    are isolated as minor isomers along with compounds of formula (Ia)    as major isomers, e.g., during column chromatography as described    herein.

Compounds of formula (C-1) are compounds of formula (C), as set forthabove in Reaction Scheme 1, where R¹ is pyrrolidin-1-yl. They can beprepared according to the method described below in relation to ReactionScheme 2:

Compounds of formula (Ca) and formula (A) are commercially available orcan be prepared according to methods described herein or known to oneskilled in the art. Compounds of formula (Ba) are compounds of formula(B), as set forth above in Reaction Scheme 1.

In general, compounds of formula (C-1) are prepared, for example, as setforth above in Reaction Scheme 2, by nitration of the benzo[7]annuleneof formula (Ca) to form the nitro compound of formula (Cb). Reductiveamination of the keto group in the ketone of formula (Cb) yields thepyrrolidine-substituted compound of formula (Cc).

Reduction of the nitro group of the pyrrolidine-substituted compound offormula (Cc), for example, by catalytic hydrogenation, gives the anilineof formula (Ba). Reaction of the aniline of formula (Ba) with diphenylcyanocarbonimidate of formula (A) yields the compound of formula (C-1).Compounds of formula (C-1) are enantiomeric. The enantiomers of compound(C-1), and similar compounds of the invention, can be isolated, forexample, by chiral phase HPLC.

Stereoselective amination of certain cyclic ketones, such as thecompounds of formula (Cb) as set forth above, can be very challenging orimpossible. Accordingly, one aspect of this invention is directed to amethod of using transaminases to produce enantiomerically pure primaryamines from cyclic ketones, particularly from cyclic ketones fused to asubstituted aromatic ring.

Transaminases (also known as amino transferases) are enzymes thatcatalyze a transamination reaction between an amino-donor molecule (suchas an amine or amino acid) and an amino-acceptor molecule (such as aketone or an α-keto acid). Specifically, enzymatic transaminationinvolves removing the amino group from the amino-donor molecule (leavingbehind a carbonyl group) and transferring the amino group to theamino-acceptor molecule (or α-keto acid) by converting the ketone moietytherein to an amine (or an amino acid). A description of transaminasesand their use in stereo-selective synthesis can be found in“Transminations. Enzyme Catalysis in Organic Synthesis (2^(nd) Edition)(2002)”, by J. David Rozzell and Andreas S. Bommarius, pp. 873-893,which is incorporated in full by reference herein.

Transaminases are particularly suitable for the enzymatic synthesis ofchiral amines from the corresponding ketone precursors. Commerciallyavailable transaminases can be used to achieve a chiral enzymaticamination of a desired starting material in the preparation of thecompounds of the invention. In particular, a ketone of the followingformula (I) where n and m are the same and are 0, 1 or 2 and R⁷ isnitro, halo or —C(O)OR² (where R² is as described above in the Summaryof the Invention) can be converted under suitable conditions to thecorresponding (S)-enantiomer and (R)-enantiomer wherein the carbon towhich the amino group is attached is either in the (S) or the (R)configuration, respectively, by utilizing a (S)-specific tranasminaseand an amino donor molecule, such as L-alanine, or a (R)-specifictransaminase and an amino donor molecule, such as L-alanine, as shownbelow:

One of ordinary skill in the art would appreciate that the amino groupon the (S)-enantiomer and the (R)-enantiomer can be furtherfunctionalized by standard procedures known to one skilled in the art.For example, treatment of the above (S)-enantiomer with1,4-dibromobutane under the appropriate alkylation conditions willresult in the amino group being converted to a 1-pyrrolidinyl group.Alternatively, treatment of the above (S)-enantiomer with an appropriateacylating agent with result in the amino group being acylatedaccordingly, and so forth.

Utilizing the appropriate transaminase to convert the cyclic ketone offormula (I) into the appropriate enantiomer, the appropriate enantiomercan be isolated in greater than 80% ee and preferably greater than 90%ee.

The following Reaction 3, where the compound of formula (Cb-1) is acompound of formula (I) as described above and PG represents a nitrogenprotecting group, illustrates a method of preparing a chiral compound ofthe invention utilizing a transaminase as described above:

Compounds of formula (Cb-1) are commercially available, or can beprepared by methods known to one skilled in the art. Compounds offormula (D-1) can be prepared according to methods known to one skilledin the art or by methods disclosed herein. The (S)-specific transaminaseis commercially available from Codexis. Preferably the (S)-specifictransaminase is ATA-103 from Codexis.

In general, compounds of formula (Ia-1) are prepared by the methoddisclosed above in Reaction Scheme 3 by first converting the ketone offormula (Cb-1) into the chiral compound of formula (Cb-2) wherein theamino group from an amino donor molecule, preferably L-alanine, istransferred to the ketone of formula (Cb-1) through an enzymatictransamination reaction under suitable conditions. In particular, theketone of formula (Cb-1) is treated with a excess molar amount of anamino donor molecule in the presence of a catalytic amount of atransaminase, preferably a (S)-specific transaminase, and astoichiometric or excess stoichiometric amount of a pyruvate reductasemixture that reduces (deactivates) the 2-keto acid side product, therebydriving the reaction into the desired direction. Preferably the pyruvatereductase mixture is PRM-102 from Codexix. The reaction is conducted atambient temperature, at a pH of between about 7.5 and about 8.0, and fora period of time of between about 24 hours and about 6 days, preferablyfor about 4 days. The chiral compound of formula (Cb-2) is isolated fromthe reaction mixture by standard isolation techniques known to oneskilled in the art.

Alternatively, the transamination reaction can be driven to completionby coupling the reaction to a second reaction that consumes the 2-ketoacid by-product in an essentially irreversible step, as described inmore detail in “Transminations. Enzyme Catalysis in Organic Synthesis(2^(nd) Edition) (2002)”, by J. David Rozzell and Andreas S. Bommarius,pp. 873-893.

The amino group of the chiral compound of formula (Cb-2) is thenprotected by standard nitrogen protecting procedures to yield thecompound of formula (Cb-3), which is isolated from the reaction mixtureby standard isolation techniques known to one skilled in the art. Thecompound of formula (Cb-3) is then treated to standard reducingconditions, such as treatment with H₂/Pd, to produce the correspondinganiline compound of formula (Cb-4), which is isolated from the reactionmixture by standard isolation techniques known to one skilled in theart. The compound of formula (Cb-4) is then treated with diphenylcyanocarbonimidate of formula (A) to produce the compound of formula(Cb-5), which is isolated from the reaction mixture by standardisolation techniques known to one skilled in the art.

The compound of (Cb-5) is then treated with a compound of formula (D-1)in the presence of an aprotic solvent, preferably toluene, at atemperature of between about 80° C. and about 100° C. for a period oftime of between about 12 hours and about 36 hours, preferably for about24 hours, to yield a compound of formula (Ia-1), which is isolated fromthe reaction mixture by standard isolation techniques known to oneskilled in the art. Compound of formula (Ia-1) is a compound of formula(Ia), as set forth above.

The protecting group on the compound of formula (Ia-1) can be removedunder standard deprotecting conditions known to one skilled in the art,such as acid hydrolysis, to produce a compound of formula (Ia-2), whichis isolated from the reaction mixture by standard isolation techniquesknown to one skilled in the art. The compound of formula (Ia-2) can befurther treated with the appropriate aldehyde or ketone under standardreductive amination conditions to yield a compound of formula (Ia-3),which is isolated from the reaction mixture by standard isolationtechniques known to one skilled in the art. Compounds of formula (D-1)utilized in Reaction Scheme 3 above are compounds of formula (D), asshown above in Reaction Scheme 1, where A is ═C(H)—. Compounds offormula (D-1) can be prepared according to the method disclosed below inReaction Scheme 4:

Compounds of formula (Da) are commercially available or can be preparedby methods known to one skilled in the art or by methods disclosedherein. In general, compounds of formula (D-1) are prepared, as setforth above in Reaction Scheme 3, by first dissolving the compound offormula (Da) (1.0 equiv) in an anhydrous aprotic polar solvent ormixture of such solvents, for example, tetrahydrofuran withhexamethylphosphoramide (HMPA) (1.2 equiv). The resulting solution isstirred at ambient temperature for about 10 minutes and then cooled to atemperature of between about −10° C. and about 5° C., preferably at 0°C. A strong base, lithium bis(trimethylsilyl)amide (Li-HMDS) (1.1equiv), is then added dropwise to the stirred mixture over a period oftime of between about 20 minutes and 40 minutes, preferably over 30minutes, while maintaining the temperature of the resulting mixture atbetween about −10° C. and about 5° C., preferably at 0° C. Ethylbromoacetate (2.5 equiv) is then added to the resulting anion of (Da)and the resulting mixture is stirred for additional period of time ofbetween about 5 minutes and 15 minutes, preferably for about 10 minutes,and then allowed to warm to ambient temperature and stirred at ambienttemperature for a period of time of between about 30 minutes and 3hours, preferably for about 2 hours. The compound of formula (Db) isthen isolated from the reaction mixture by standard isolation techniquesknown to one skilled in the art, such as solvent evaporation andpurification by flash column chromatography.

The compound of formula (Db) is then treated under basic hydrolysisconditions to form the compound of formula (Dc), which is isolated fromthe reaction mixture by standard isolation techniques known to oneskilled in the art.

The compound of formula (Dc) (1.0 equiv) is then treated with hydrazinehydrate (1.25 equiv) in the presence of a polar protic solvent, such asethanol, to yield the compound of formula (Dd), which is isolated fromthe reaction mixture by standard isolation techniques known to oneskilled in the art.

A mixture of the compound of formula (Dd) (1.0 equiv) and anhydrouscopper(II) chloride (2.0 equiv) is then refluxed in acetonitrile toyield the unsaturated compound of formula (De), which is isolated fromthe reaction mixture by standard isolation techniques known to oneskilled in the art.

A mixture of the compound of formula (De) and phosphoryl chloride, isrefluxed for a period of time of between about 1 hour and 3 hours,preferably for about 2 hours to aromatize and chlorinate the ringcontaining the N—N linkage. After cooling to ambient temperature, thecompound of formula (Df) is isolated from the reaction mixture bystandard isolation techniques known to one skilled in the art.

A mixture of the compound of formula (Df) (1.0 equiv) and anhydroushydrazine (19.8 equiv) in a protic solvent, such as ethanol, is refluxedfor a period time of between about 4 hours and 24 hours, preferably forabout 16 hours. After cooling to ambient temperature, water is added tothe mixture and the compound of formula (D-1) is then isolated from thereaction mixture by standard isolation techniques known to one skilledin the art.

All compounds of the invention which exist in free base or acid form canbe converted to their pharmaceutically acceptable salts by treatmentwith the appropriate inorganic or organic base or acid by methods knownto one of ordinary skill in the art. Salts of the compounds of theinvention can be converted to their free base or acid form by standardtechniques known to one skilled in the art.

The following specific Synthetic Preparations (for intermediates) andSynthetic Examples (for compounds of the invention) are provided as aguide to assist in the practice of the invention, and are not intendedas a limitation on the scope of the invention. The number following eachcompound below refers to its number in Table 1 and Table 2, as discussedin more detail below.

Synthetic Preparation 1 Synthesis of7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene A compound of formula (Ca)

A. Sodium methoxide (9.4 g, 174.2 mmol) was added to a 250 mL of flaskwith dry methanol (100 mL) at 0° C. After the solid was dissolved, theresulting solution was warmed to ambient temperature and was added to asolution of dimethyl acetone-1,3-dicarboxylate (15.2 g, 87.1 mmol) ando-xylylene dibromide (20 g, 75.7 mmol) in 100 mL of dry THF at 0° C.dropwise within 30 min. After the addition, the reaction mixture waswarmed to ambient temperature and stirred overnight. The volatiles wereevaporated, the residue was poured into 40 mL of 10% HCl solution andextracted with ethyl acetate (EtOAc) (200 mL×2). The combined extractswere washed with water, saturated NaHCO₃ solution and brine. Afterevaporation, the residual oil was used for next step directly.

B. The crude dimethyl7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6,8-dicarboxylate wasdissolved in 200 mL of ethanol (EtOH) and then 100 mL of 2 N KOH. Theresulting mixture was refluxed at 85° C. for 17 h. After cooling toambient temperature, the volatiles were evaporated. To the residue wasadded 120 mL of 2N HCl at 0° C., the crude product was extracted byEtOAc (200 mL×2). The combined extracts were washed with brine. Afterbeing dried (MgSO₄), filtered, and concentrated, the residue waspurified by flash column chromatography on silica gel (hexanes/EtOAc8:1) to afford 6.6 g (57%) of7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene as a white solid: mp 40-41°C.; ¹H NMR (300 MHz, CDCl₃) δ: 7.21 (m, 4H), 2.94-2.90 (m, 4H),2.63-2.60 (m, 4H); LC-MS: 161 (M+H)⁺.

Synthetic Preparation 2 Synthesis of2-nitro-8,9-dihydro-5H-benzo[7]annulene-7(6H)-one A Compound of Formula(Cb)

To a solution of cold (0° C.) concentrated sulfuric acid (15 mL) wasadded 70% nitric acid (15 mL) dropwise over 30 min. The addition wascontrolled to maintain the internal reaction temperature below 5° C.After the addition, the resulting solution was transferred into anaddition funnel and was added dropwise to a solution of7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene (14 g, 87.5 mmol) innitromethane (80 mL) at 0° C. over a period of 40 min. After theaddition, the reaction mixture was stirred at 0° C. for 2 h. Then icewater (˜80 mL) was added to the reaction mixture, and the mixture wasstirred for additional 30 min. Then the mixture was transferred to aseparatory funnel where the layers were separated. The aqueous layer wasextracted with ethyl acetate (3×80 mL). The combined layers were washedwith cold water, sat. NaHCO₃ solution and brine. After being dried(MgSO₄), filtered, and concentrated, the residue was purified by flashcolumn chromatography on silica gel (hexanes/EtOAc=3:1 to 2:1) to affordthe mixture of nitro regioisomers (˜15 g), which was then purified byrecrystallization from MTBE (tert-butyl methyl ether, 180 mL) to yield7.3 g of 2-nitro-8,9-dihydro-5H-benzo[7]annulene-7(6H)-one (40% yield)as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ: 8.10-8.06 (m, 2H),7.40-7.37 (m, 1H), 3.04-3.00 (m, 4H), 2.67-2.65 (m, 4H); LC-MS: 206(M+H)⁺.

Synthetic Preparation 3 Synthesis of1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine ACompound of Formula (Cc)

Pyrrolidine (0.85 g, 12 mmol) and2-nitro-7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene (2.05 g, 10 mmol)were mixed in 1,2-dchloroethane (35 mL) and then treated with NaBH(OAc)₃(3.18 g, 15 mmol) and AcOH (0.60 g, 10 mmol). The mixture was stirred atambient temperature under a N₂ atmosphere overnight. The reactionmixture was quenched with saturated NaHCO₃, and the product wasextracted with EtOAc (3×30 mL). The organic layers were combined anddried over NaSO₄. The solvent was evaporated and the residue waspurified by flash column chromatography eluting with CH₂Cl₂/DMA=1/1(DMA=CH₂Cl₂/MeOH/30% NH₃=80/19/1) to afford1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine, ayellow oil (2.2 g, 85%); MS (m/e): 261 (M+H⁺).

Synthetic Preparation 4 Synthesis of1-(2-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine ACompound of Formula (Ba)

A mixture of1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine (2.0g; 7.69 mmol) and 10% palladium on carbon (0.2 g, ˜50% water) inmethanol (150 mL) was shaken under hydrogen (40 psi) for 1 h. After thistime the reaction mixture was filtered through diatomaceous earth andthe filtrate was concentrated under reduced pressure to afford1-(2-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine as anoil (quantitative yield); MS (m/e): 231 (M+H⁺).

Synthetic Preparation 5 Synthesis of PhenylN′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidateA Compound of Formula (C-1)

A mixture of1-(2-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine (1.7g; 7.39 mmo) and diphenyl cyanocarboimidate (1.76 g, 7.39 mmol) in 20 mLof isopropanol was stirred at ambient temperature overnight. The solidwas filtered, washed with isopropanol and ether and dried to give phenylN′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate,as a white solid (2.2 g, 80%). MS (m/e): 375 (M+H⁺).

Synthetic Preparation 6 Isolation of Phenyl(S)—N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidateand Phenyl(R)—N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidateEnantiomers of the Compound of Formula (C-1)

PhenylN′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate(0.43 g, racemic) was eluted on a chiral column chromatography mobilephase; ethanol/MeOH/triethyl amine=1/1/0.2% to afford phenyl(S)—N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidateand phenyl(R)—N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate:Chiral column: Chiralcel OJ, 21.2×250 mm. 10 μM; packing material:cellulose tris-(4-methylbenzoate) coated on 10 μm silica gel substrate.Flow rate 9.9 mL/min, sample solubility 30 mg/mL in methanol. Singleenantiomers were isolated in 170 mg and 190 mg quantities, respectively.Absolute configuration of each enantiomer was not determined at thistime.

Synthetic Preparation 7 Synthesis of ethyl2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetate Compound ofFormula (Db)

To a mixture of 1-benzosuberone (5.0 g, 31.2 mmol, Aldrich) in drytetrahydrofuran (THF) (20 mL) was added hexamethylphosphoramide (6.5 mL,37.5 mmol) (99%, Aldrich). The resulting mixture was stirred at ambienttemperature for 10 min and then cooled to 0° C. with a ice-water bath,1.0 M solution of lithium bis(trimethylsilyl)-amide in THF (32.7 mL,32.7 mmol) was added dropwise in 30 min. After the addition, thereaction mixture was stirred at 0° C. for 30 min. Ethyl bromoacetate(8.7 mL, 78.1 mmol) was then added. After stirring for a further 10 min,the reaction mixture was warmed to ambient temperature and stirred for 2h. Solvent was evaporated, the residue was diluted with ethyl acetate(EtOAc) (300 mL), and washed with water and brine. After being dried(MgSO₄), filtered, and concentrated, the residue was purified by flashcolumn chromatography eluting with hexanes-ethyl acetate 6:1→4:1) toafford 6.6 g of the compound of formula (Db), ethyl2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetate, as anorange oil (84%), ¹H NMR (300 MHz, CDCl₃) δ: 7.69-7.21 (m, 4H),4.22-4.05 (m, 2H), 3.40-3.30 (m, 1H), 3.12-2.92 (m, 3H), 2.52-2.43 (m,1H), 2.20-1.58 (m, 4H), 1.28-1.21 (m, 3H); LC-MS: purity: 91.8%; MS(m/e): 247 (MH⁺).

Synthetic Preparation 8 Synthesis of2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetic acidCompound of Formula (Dc)

The compound of formula (Db), ethyl2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetate, (6.6 g,26.8 mmol) was dissolved in ethanol (EtOH) (30 mL), then 10% potassiumhydroxide (KOH) aqueous solution (37.5 mL, 67 mmol) was added and theresulting mixture was refluxed for 2 h. After cooling to ambienttemperature, the EtOH was removed by evaporation. The residue wasextracted with EtOAc twice (15 mL×2). The aqueous layer was thentransferred into a flask and cooled with an ice-water bath, con. HCl wasadded dropwise to adjust pH to about 2.0. EtOAc (60 mL) was then added,the layers were separated, and the aqueous layer was extracted withEtOAc. The combined extracts were washed with brine. After being dried(MgSO₄), filtered, and concentrated, the compound of formula (Dc),2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetic acid, wasobtained as an orange oil (5.7 g, 97%); ¹H NMR (300 MHz, CDCl₃) δ:7.71-7.68 (m, 1H), 7.41-7.20 (m, 3H), 3.37-3.31 (m, 1H), 3.12-2.91 (m,3H), 2.57-2.49 (m, 1H), 2.15-1.90 (m, 2H), 1.75-1.62 (m, 2H); LC-MS:purity: 100%; MS (m/e): 219 (MH⁺).

Synthetic Preparation 9 Synthesis of4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-oneCompound of Formula (Dd)

A. A mixture of the compound of formula (Dc),2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetic acid, (5.7g, 26.1 mmol) and hydrazine hydrate (1.6 mL, 32.7 mmol) in 20 mL ofethanol was refluxed for 2 h, cooled and filtered (washed with smallamount of EtOH) to give the compound of formula (Dd),4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one, as awhite solid (4.7 g, 84%); ¹H NMR (300 MHz, CDCl₃) δ: 8.61 (bs, 1H),7.53-7.14 (m, 4H), 2.98-2.75 (m, 3H), 2.58 (dd, J=15.3, 16.8 Hz, 1H),2.31 (dd, J=12.0, 16.8 Hz, 1H), 1.96-1.59 (m, 4H); LC-MS: purity: 100%;MS (m/e): 215 (MH⁺).

B. Alternatively, a mixture of benzosuberone (10.6 g, 66.2 mmol),glyoxylic acid monohydrate (6.08 g, 66.2 mmol), sodium hydroxide (10.6g, 265 mmol), ethanol (40 mL) and water (100 mL) were stirred overnightat ambient temperature, and then heated under reflux for 1 h. Themixture was cooled, then diluted with water and extracted twice withdichloromethane (subsequently discarded). The aqueous layer was thenacidified with 10% aqueous hydrochloric acid. Ice was added for cooling.The mixture was then filtered to give a pale yellow solid, 10.5 g (afterair drying). The crude solid was then heated at 100° C. for 1 h with amixture of acetic acid (60 mL), water (30 mL) and zinc dust (6 g). Thereaction mixture was cooled to ambient temperature and filtered. Thefiltrate was extracted with ethyl acetate. The organic layer was washedthree times with saturated sodium chloride solution, then dried overanhydrous sodium sulfate and concentrated under vacuum. The cruderesidue was heated with ethanol (25 mL) and hydrazine monohydrate (10mL) under reflux for 3 h. The solvent was removed under vacuum and theresidue was crystallized from benzene/ethanol, 1/1, to give4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one as awhite solid, 2.31 g; ¹H NMR (CDCl₃, 300 MHz) 8.66 (s, 1H), 7.52 (d, 1H),7.24-7.50 (m, 2H), 7.16 (d, 2H), 2.75-3.00 (m, 3H), 2.56 (dd, 1H), 2.31(dd, 1H), 1.60-1.90 (m, 4H) ppm; MS (ES) 215 (M+H). This procedurefollowed that reported by V. Peesapati and S.C. Venkata, Indian J.Chem., 41B, 839 (2002).

Synthetic Preparation 10 Synthesis of6,7-dihydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3(5H)-one Compoundof Formula (De)

A. A mixture of the compound of formula (Dd),4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one (4.7g, 22 mmol) and anhydrous copper(II) chloride (6 g, 44 mmol) wasrefluxed in acetonitrile (45 mL) for 2 hours. After cooling to ambienttemperature, the mixture was poured into ice-water (200 g) and the solidobtained was washed with 10% HCl solution twice (about 20 mL×2) and coldwater twice (about 20 mL×2). After freeze-drying, the compound offormula (De),6,7-dihydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3(5H)-one (4.2 g,90%) was obtained as a white solid, ¹H NMR (300 MHz, CDCl₃) δ: 10.80(bs, 1H), 7.53-7.21 (m, 4H), 6.77 (s, 1H), 2.66 (t, J=6.9 Hz, 2H), 2.45(t, J=6.9 Hz, 2H), 2.14 (quant, J=6.9 Hz, 2H); LC-MS: purity: 100%; MS(m/e): 213 (MH⁺).

B. Alternatively, a solution of4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one (2.31g, 10.74 mmol), sodium m-nitrobenzenesulfonate (2.48 g, 11 mmol), sodiumhydroxide (1.86 g, 46.5 mmol) in water (80 mL) was heated under refluxfor 1.5 h. The solution was cooled to ambient temperature, and thenacidified with concentrated hydrochloric acid. The solid whichprecipitated was filtered off, washed with water and crystallized fromethanol to give6,7-dihydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3(5H)-one as tancrystals, 1.46 g; ¹H NMR (DMSO-d₆, 300 MHz) 13.04 (s, 1H), 7.25-7.45 (m,4H), 6.78 (s, 1H), 2.49 (m, 2H), 2.35 (m, 2H), 2.04 (m, 2H) ppm; MS (ES)213 (M+H).

Synthetic Preparation 11 Synthesis of3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine Compoundof Formula (Df)

A. A mixture of the compound of formula (De),6,7-dihydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3(5H)-one (4.0 g,19.3 mmol) and POCl₃ (20 mL) was refluxed for 2 h. After cooling toambient temperature, the volatiles were evaporated. The residue waspoured into a mixture of ice water and sodium bicarbonate, CH₂Cl₂ (200mL) was added to dissolve the solid. The layers were separated, and theaqueous layer was extracted with CH₂Cl₂ one more time. The combinedorganic layers were washed with brine. After being dried (MgSO₄),filtered, and concentrated, the compound of formula (Df),3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine wasobtained as a yellow solid (4.3 g, 99%), ¹H NMR (300 MHz, CDCl₃) δ: 7.82(m, 1H), 7.45-7.24 (m, 4H), 2.59-2.51 (m, 4H), 2.27 (quant, J=6.9 Hz,2H); LC-MS: purity: 100%; MS (m/e): 231 (MH⁺).

B. Alternatively,6,7-dihydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3(5H)-one was heatedwith 20 mL of phosphorus (III) oxychloride at 100° C. for 4.75 h. Thesolvent was removed under vacuum. The residue was treated with ice andsaturated sodium bicarbonate solution. The solid which formed wasfiltered off, washed well with water and air-dried to yield thecorresponding3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (1.6 g);¹H NMR (CDCl₃, 300 MHz) 7.82 (m, 1H), 7.44 (m, 2H), 7.39 (s, 1H), 7.27(m, 1H), 2.55 (m, 4H), 2.32 (m, 2H) ppm; MS (ES) 231/233 (M+H).

Synthetic Preparation 12 Synthesis of3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazineCompound of Formula (D-1)

A. A mixture of the compound of formula (Df),3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine, (4.3 g,18.6 mmol) and anhydrous hydrazine (11.7 mL, 370 mmol) in 45 mL ofethanol was refluxed for 16 h. After cooling to ambient temperature, 5mL of water was added and the volatiles were then evaporated. To thesolid residue was added cold water (about 80 mL). After sonication for10 min, the resulting solid was collected by filtration and washed withcold water three times. After freeze-drying, the compound of formula(D-1), 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine,(4.14 g, 98%) was obtained as a slight yellow solid, ¹H NMR (300 MHz,CD₃OD) δ: 7.59 (m, 1H), 7.39-7.26 (m, 3H), 7.04 (s, 1H), 2.54 (t, J=6.9Hz, 2H), 2.47 (t, J=6.9 Hz, 2H), 2.18 (quant, J=6.9 Hz, 2H); LC-MS:purity: 100%; MS (m/e): 227 (MH⁺).

B. Alternatively,3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (1.6 g)was heated with anhydrous hydrazine (4 mL) in ethanol (50 mL) at 100° C.for 4.75 h. The solvent was removed under vacuum. The residue waspartitioned between chloroform and 1M saturated aqueous potassiumcarbonate. The organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum to give3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine as abrown solid; ¹H NMR (CDCl₃, 300 MHz) 7.74 (m, 1H), 7.30 (m, 2H), 7.17(m, 1H), 6.92 (s, 1H), 2.49 (m, 2H), 2.39 (m, 2H), 2.12 (m, 2H) ppm; MS(ES) 227 (M+H).

Synthetic Preparation 13 Synthesis of PhenylN′-cyano-N-(7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate(Cb-5)

Finely ground 2-Nitro-8,9-dihydro-5H-benzo[7]annulen-7(6H)-one (8.00 g,39.0 mmol) and L-alanine (34.7 g, 390 mmol) were added to the reactionbuffer (1000 mL, Codexis/BioCatalytics). The mixture was stirredvigorously for about 20 min in order to obtain a uniform suspension(bright-yellow in color). The pyruvate reductase mix (40.0 g, PRM-102,Codexis/BioCatalytics) and the transaminase (0.85 g, ˜10.6 wt %,ATA-103) were added. The pH of the reaction mixture was ˜7. Stirring wascontinued at a slow pace; the pH was checked once a day and, ifnecessary, adjusted to pH 7.0-7.5 using 1M NaOH. During the course ofthe reaction the color of the mixture changed to a yellow-orange color.After 6 days HPLC analysis showed 99% conversion. The reaction wasworked up by adding sat. NaHCO₃ solution (200 mL) and CHCl₃ (600 mL).This mixture was stirred vigorously to ensure complete transfer of theproduct into the organic phase. After stirring overnight two layers hadformed and the organic layer contained large amounts of a gel-likesolid. The organic layer was separated and filtered through a largeglass frit (medium) to remove the gel-like solid. The aqueous phase wasextracted three times with DCM. The combined organic layers werefiltered through MgSO₄ and the solvents were evaporated to give thedesired amine, (7S)-2-nitro-7-amino-7,8,9-trihydro-5H-benzo[7]annulene(7.27 g, 91%, dark-red oil).

The single enantiomer was then BOC-protected, the nitro group reduced bytreatment with H₂/Pd and the primary aniline treated with diphenylcyanocarboimidate (slight excess) in 20 mL of isopropanol with stirringat ambient temperature overnight. The solid was filtered, washed withisopropanol and ether and dried to give phenyl(7S)-N′-cyano-N-(7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate,as a white solid in high yield (from the single enantiomer viatransamination).

Synthetic Example 1 Synthesis of1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine

PhenylN′-cyano-N-(7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate(2.00 g, 4.75 mmol) and3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (1.08g, 4.75 mmol) were mixed in dry toluene (40 ml). The suspension washeated to 90° C. and stirred for 24 h. The clear solution was allowed tocool to ambient temperature and the toluene was evaporated using arotavapor. The crude product was then checked by HPLC and TLC. Columnchromatography on silica gel using CHCl₃ and 5% NH₃ (2M in MeOH)afforded some clean fractions of product which gave 367 mg (14%) of thedesired product,1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.The impure fractions were further purified by reverse phase HPLC toyield another 515 mg (20%) of the desired product, compound #13, ¹H NMR(DMSO-d₆, 300 MHz) 9.04 (s, 1H, NH), 7.92 (s, 1H), 7.86 (s, 2H), 7.69(m, 1H), 7.43 (m, 3H), 7.34 (m, 1H), 7.23 (m, 1H), 6.96 (d, 1H), 6.83(d, 1H), 3.49 (m, 1H), 2.72-2.39 (m, 8H), 2.22 (m, 2H), 2.07 (s, 1H),1.92 (m, 2H), 1.38 (s, 9H), 1.17 (m, 2H) ppm; trifluoroacetic acid saltMS (ES) 553.24 (M+H), 551.42 (M−H).

Synthetic Example 2

The following compounds of the invention were prepared according to themethods similar to those described herein:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(acetamido)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #1, ¹H-NMR (DMSO-d6, 300 MHz) 9.07 (s, 1H), 7.93 (s, 1H),    7.90-7.65 (m, 3H), 7.47-7.31 (m, 3H), 7.24 (s, 1H), 7.00 (d, 1H),    3.89-3.80 (m, 1H), 2.71-2.50 (m, 8H), 2.30-2.19 (m, 2H), 1.96-1.88    (m, 2H), 1.80 (s, 3H), 1.37-1.19 (m, 2H) ppm; MS (ES) 495.21 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(methoxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #2, ¹H-NMR (CDCl₃, 300 MHz) 8.90-8.78 (m, 1H), 8.48 (bs,    2H), 7.93 (s, 1H), 7.80-7.78 (m, 1H), 7.47-7.41 (m, 2H), 7.38-7.30    (m, 3H), 7.05-7.00 (m, 1H), 3.82 (s, 3H), 3.80-3.64 (m, 2H),    2.94-2.81 (m, 3H), 2.79-2.71 (m, 4H), 2.70-2.67 (m, 3H), 2.38-2.43    (m, 4H), 2.38-2.29 (m, 3H), 1.80-1.60 (m, 2H) ppm; MS (ES) 565.29    (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4,4-difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #3, ¹H-NMR (DMSO-d6, 300 MHz) 9.60 (s, 1H), 9.11 (s, 1H),    7.92 (s, 1H), 7.85 (s, 1H), 7.71-7.68 (m, 1H), 7.51-7.45 (m, 2H),    7.39-7.33 (m, 2H), 7.08 (d, 1H), 3.67 (t, 1H), 3.52 (d, 2H), 3.18    (bs, 2H), 2.84-2.52 (m, 6H), 2.37-2.22 (m, 8H), 1.58-1.41 (m, 3H)    ppm; MS (ES) 557.23 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #4, ¹H-NMR (DMSO-d6, 300 MHz) 9.62 (s, 1H), 9.11 (s, 1H),    7.92 (s, 1H), 7.81 (s, 1H), 7.78-7.71 (m, 1H), 7.45-7.41 (m, 2H),    7.38-7.32 (m, 1H), 7.04 (d, 1H), 4.37 (d, 1H), 4.11 (d, 1H), 3.78    (s, 2H), 3.59 (t, 1H), 2.81-2.74 (m, 4H), 2.65-2.57 (m, 7H),    2.31-2.21 (m, 3H), 1.59-1.40 (m, 2H) ppm; MS (ES) 539.21 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #5, ¹H-NMR (DMSO-d6, 300 MHz) 9.55 (s, 1H), 9.18 (s, 1H),    7.94 (s, 1H), 7.72-7.68 (m, 1H), 7.47-7.40 (m, 2H), 7.38-7.31 (m,    2H), 7.05 (d, 1H), 5.05-4.70 (bs, 3H), 4.55 (q, 1H), 3.64 (t, 1H),    3.52-3.48 (m, 1H), 3.31-3.25 (m, 1H), 2.80-2.70 (m, 3H), 2.62-2.52    (m, 3H), 2.39-2.20 (m, 5H), 2.09-1.78 (m, 4H), 1.49-1.38 (m, 3H)    ppm; MS (ES) 551.27 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #6, ¹H-NMR (DMSO-d6, 300 MHz) 9.11 (s, 1H), 8.97-8.90 (m,    1H), 7.94 (s, 1H), 7.85 (s, 1H), 7.71-7.68 (m, 1H), 7.50-7.40 (m,    2H), 7.38-7.30 (m, 2H), 7.05 (d, 1H), 4.09 (q, 2H), 3.55 (t, 1H),    3.38 (d, 1H), 3.10 (q, 1H), 2.85-2.57 (m, 5H), 2.52-2.42 (m, 6H),    2.29-2.18 (m, 3H), 2.06 (d, 2H), 1.77-1.70 (m, 2H), 1.54-1.36 (m,    3H), 1.29 (t, 3H) ppm; MS (ES) 593.28 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #7, ¹H-NMR (DMSO-d6, 300 MHz) 9.90 (bs, 1H), 9.10 (s, 1H),    7.96 (s, 2H), 7.74-7.69 (m, 1H), 7.50-7.41 (m, 2H), 7.37-7.40 (m,    1H), 7.05 (d, 1H), 4.40-3.83 (m, 5H), 3.53-3.44 (m, 1H), 3.36 (d,    1H), 3.12-2.98 (m, 1H), 2.83-2.71 (m, 2H), 2.62-2.59 (m, 1H),    2.57-2.43 (m, 7H), 2.41-2.36 (m, 1H), 2.29-2.20 (m, 1H), 2.02-1.91    (m, 2H), 1.50-1.38 (m, 1H) ppm; MS (ES) 565.26 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((carboxymethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #8, ¹H-NMR (DMSO-d6, 300 MHz) 9.42 (s, 1H), 9.10 (s, 1H),    7.95 (s, 1H), 7.87 (s, 1H), 7.73-7.68 (m, 1H), 7.48-7.41 (m, 2H),    7.39-7.33 (m, 2H), 7.05 (d, 1H), 4.10 (bs, 3H), 3.57 (t, 1H), 2.78    (s, 3H), 2.68-2.45 (m, 9H), 2.3.4-2.22 (m, 3H). 1.55-1.39 (m, 2H)    ppm; MS (ES) 525.22 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #9, ¹H-NMR (DMSO-d6, 300 MHz) 9.21 (s, 1H), 9.12 (s, 1H),    7.93 (s, 1H), 7.87 (s, 1H), 7.73-7.69 (m, 1H), 7.49-7.41 (m, 3H),    7.38-7.32 (m, 2H), 7.06 (d, 1H), 4.11 (q, 2H), 3.54-3.29 (m, 5H),    3.13-2.97 (m, 4H), 2.80-2.70 (m, 8H), 2.60 (t, 2H), 2.37-2.22 (m,    4H), 1.53-1.39 (m, 2H), 1.26 (t, 3H) ppm; MS (ES) 608.31 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #10, MS (ES) 580.25 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #11, MS (ES) 507.24 (M+H), 505.33 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #12, MS (ES) 507.25 (M+H), 505.28 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #14, MS (ES) 553.31 (M+H), 551.47 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #15, formic acid salt ¹H NMR (DMSO-d₆, 300 MHz) 9.11 (s,    1H, NH), 7.93 (s, 1H), 7.65 (m, 3H), 7.72 (d, 1H), 7.47 (m, 2H),    7.38 (s, 1H), 7.27 (s, 1H), 7.03 (d, 1H), 3.32 (s, 1H), 2.71 (m,    4H), 2.65-2.45 (m, 4H), 2.21 (m, 4H), 1.29 (m, 2H) ppm; MS (ES)    553.65 (M+H), 551.37 (M−H); free base MS (ES) 453.65 (M+H), 451.39    (M−H); trifluoroacetic acid salt MS (ES) 453.14 (M+H), 451.23 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7s)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #16, ¹H NMR (DMSO-d₆, 300 MHz) 9.12 (s, 1H, NH), 7.95 (s,    1H), 7.82 (s, 2H, NH₂), 7.71 (m, 1H), 7.45 (m, 3H), 7.31 (m, 2H),    7.05 (d, 2H), 3.75 (t, 1H), 2.96 (m, 4H), 2.73 (m, 4H), 2.65-2.42    (m, 4H), 2.23 (m, 4H), 1.31 (m, 2H), 1.08 (s br, 2H), 0.61 (d, 4H),    0.29 (d, 4H) ppm; MS (ES) 561.30 (M+H), 559.42 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-methylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #17, ¹H NMR (DMSO-d₆, 300 MHz): 9.13 (s, 1H), 8.25 (s br,    2H), 7.81-8.00 (m, 3H), 7.66-7.76 (m, 1H), 7.41-7.53 (m, 3H),    7.27-7.39 (m, 2H), 6.97-7.11 (m, 1H), 3.19-3.47 (m, 1H), 2.66-2.86    (m, 6H), 2.43-2.65 (m, 7H), 2.14-2.37 (m, 4H), 1.82-1.99 (m, 1H),    1.20-1.47 (m, 2H), 0.93 (d, J=6.6 Hz, 6H) ppm; MS (ES) 509.23 (M+H),    507.36 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((propyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #18, ¹H NMR (DMSO-d₆, 300 MHz): 9.06-9.18 (m, 1H),    8.19-8.40 (m, 2H), 7.76-7.99 (m, 3H), 7.23-7.54 (m, 5H), 7.03 (d,    1H), 3.20-3.44 (m, 1H), 2.83-3.00 (m, 2H), 2.66-2.82 (m, 4H),    2.51-2.66 (m, 4H), 2.11-2.34 (m, 4H), 1.46-1.73 (m, 2H), 1.19-1.44    (m, 2H), 0.91 (s, 3H) ppm; MS (ES) 495.24 (M+H), 493.38 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #19, ¹H NMR (DMSO-d₆, 300 MHz): 9.12 (s, 1H), 8.67-8.85 (m,    1H), 7.77-8.02 (m, 3H), 7.65-7.76 (m, 1H), 7.25-7.56 (m, 5H), 7.05    (d, J=8.3 Hz, 1H), 3.47-3.70 (m, 1H), 2.99-3.18 (m, 2H), 2.83-2.98    (m, 2H), 2.66-2.83 (m, 4H), 2.50-2.66 (m, 5H), 2.10-2.34 (m, 4H),    1.34-1.78 (m, 6H), 0.88 (t, J=7.2 Hz, 5H) ppm; MS (ES) 537.30 (M+H),    535.49 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #20, ¹H NMR (DMSO-d₆, 300 MHz): 9.10 (s, 1H), 7.94 (s, 1H),    7.83 (s br, 2H), 7.67-7.75 (m, 1H), 7.41-7.53 (m, 3H), 7.29-7.41 (m,    2H), 7.05 (d, 1H), 3.52-3.68 (m, 2H), 2.93-3.27 (m, 4H), 2.66-2.85    (m, 4H), 2.50-2.65 (m, 4H), 2.11-2.31 (m, 5H), 1.33-1.60 (m, 2H),    1.09-1.29 (m, 7H) ppm; MS (ES) 509.23 (M+H), 507.35 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #21, MS (ES) 535.30 (M+H), 533.46 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #22, MS (ES) 521.28 (M+H), 519.28 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((1-cyclopentylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #23, MS (ES) 563.30 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-propylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #24, ¹H NMR (DMSO-d₆, 300 MHz): 9.09 (s, 1H), 8.32 (s, 1H),    7.94 (s, 1H), 7.84 (s, 2H), 7.63-7.77 (m, 1H), 7.40-7.52 (m, 2H),    7.36 (s br, 1H), 7.28 (s, 1H), 7.01 (d, 1H), 3.16-3.35 (m, 2H),    3.10-3.16 (m, 1H), 2.65-2.80 (m, 4H), 2.56-2.65 (m, 2H), 2.07-2.33    (m, 5H), 1.19-1.40 (m, 2H), 1.16 (d, J=6.3 Hz, 6H) ppm; MS (ES)    495.26 (M+H), 493.37 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((3,3-dimethylbut-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #25, MS (ES) 536.18 (M);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #26, MS (ES) 549.28 (M+H), 547.29 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #27, MS (ES) 645.43 (M+H), 643.51 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((5-chlorothien-2-yl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #28, ¹H NMR (DMSO-d₆, 300 MHz): 9.12 (s, 1H), 8.86 (s br,    2H), 7.66-7.99 (m, 3H), 7.26-7.53 (m, 4H), 7.17 (d, 2H), 7.04 (d,    1H), 4.43 (s br, 2H), 3.21-3.36 (m, 2H), 2.65-2.86 (m, 7H),    2.13-2.39 (m, 4H), 1.17-1.50 (m, 2H) ppm; MS (ES) 583.15 (M+H),    581.28 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-carboxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1    ,2,4-triazole-3,5-diamine, compound #29, MS (ES) 587.26 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((3-bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #30, ¹H NMR (DMSO-d₆, 300 MHz): 9.09 (s, 1H), 8.01 (s, 1H),    7.67-7.96 (m, 6H), 7.27-7.50 (m, 5H), 7.03 (d, 1H), 6.50 (s, 1H),    4.12 (s br, 1H), 3.05-3.20 (m, 3H), 2.65-2.79 (m, 4H), 2.55-2.64 (m,    2H), 2.15-2.37 (m, 4H), 1.17-1.46 (m, 3H) ppm; MS (ES) 623.00 (M+H),    619.06 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #31, ¹H NMR (DMSO-d₆, 300 MHz): 9.06 (s, 1H), 8.25 (s br,    2H), 7.81-8.01 (m, 3H), 7.65-7.78 (m, 2H), 7.25-7.51 (m, 2H),    6.97-7.08 (m, 1H), 4.86-5.00 (m, 1H), 3.99-4.08 (m, 1H), 2.66-2.85    (m, 2H), 2.52-2.65 (m, 4H), 2.15-2.36 (m, 5H), 1.87-2.12 (m, 5H),    1.12-1.48 (m, 3H) ppm; MS (ES) 481.10 (M+H), 479.13 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #32, MS (ES) 507.15 (M+H), 505.24 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-pentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #33, MS (ES) 523.16 (M+H), 521.27 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2,2-dimethylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #34, ¹H NMR (DMSO-d₆, 300 MHz): 9.05 (s, 1H), 8.29 (s, 1H),    7.93 (s, 1H), 7.85 (s br, 2H), 7.61-7.75 (m, 1H), 7.32-7.49 (m, 3H),    7.28 (s, 1H), 6.99 (d, 1H), 2.82-2.96 (m, 1H), 2.65-2.78 (m, 3H),    2.56-2.65 (m, 2H), 2.36-2.54 (m, 5H), 2.17-2.33 (m, 2H), 1.99-2.16    (m, 2H), 1.15-1.42 (m, 2H), 0.88 (s, 9H) ppm; MS (ES) 523.16 (M+H),    521.26 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #35, MS (ES) 617.28 (M+H), 615.31 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #36, ¹H NMR (DMSO-d₆, 300 MHz): 9.07 (s, 1H), 8.34 (s, 1H),    7.94 (s, 1H), 7.84 (s br, 2H), 7.66-7.75 (m, 1H), 7.33-7.53 (m, 3H),    7.28 (s, 1H), 7.00 (d, 1H), 2.87-3.13 (m, 1H), 2.40-2.84 (m, 10H),    1.92-2.33 (m, 5H), 1.63-1.80 (m, 2H), 1.39-1.63 (m, 4H), 1.05-1.38    (m, 4H) ppm; MS (ES) 535.18 (M+H), 533.16 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #37, MS (ES) 665.26 (M+H), 663.40 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #38, ¹H NMR

(DMSO-d₆, 300 MHz): 9.03 (s, 1H), 8.32 (s, 1H), 7.92 (s, 1H), 7.83 (sbr, 2H), 7.63-7.75 (m, 1H), 7.32-7.55 (m, 3H), 7.27 (s, 1H), 6.99 (d,1H), 6.08-6.21 (m, 1H), 5.89-6.01 (m, 1H), 2.83-3.03 (m, 2H), 2.65-2.82(m, 4H), 2.54-2.65 (m, 4H), 2.29-2.44 (m, 4H), 1.93-2.33 (m, 6H), 1.81(t, 1H), 1.14-1.37 (m, 4H), 0.39-0.60 (m, 1H) ppm; MS (ES) 559.17 (M+H),557.39 (M−H);

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-methylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #39, ¹H NMR (DMSO-d₆, 300 MHz): 9.08 (s, 1H), 8.34 (s, 1H),    7.93 (s, 1H), 7.86 (s br, 2H), 7.67-7.74 (m, 1H), 7.40-7.51 (m, 3H),    7.33-7.39 (m, 1H), 7.29 (s br, 1H), 7.01 (d, J=8.3 Hz, 1H), 3.08 (s    br, 1H), 2.52-2.87 (m, 10H), 2.07-2.33 (m, 4H), 1.52-1.68 (m, 1H),    1.35-1.48 (m, 2H), 1.17-1.34 (m, 2H), 0.87 (d, J=6.3 Hz, 6H) ppm; MS    (ES) 523.20 (M+H), 521.27 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #40, ¹H NMR (DMSO-d₆, 300 MHz): 9.01 (s, 1H), 7.91 (s, 1H),    7.83 (s br, 2H), 7.67-7.74 (m, 1H), 7.39-7.49 (m, 3H), 7.33-7.39 (m,    1H), 7.25-7.31 (m, 1H), 6.99 (d, J=8.3 Hz, 1H), 2.52-2.75 (m, 9H),    2.16-2.38 (m, 7H), 1.86-2.04 (m, 2H), 1.49-1.62 (m, 2H), 1.11-1.28    (m, 5H), 0.83 (d, J=6.6 Hz, 12H) ppm; MS (ES) 593.28 (M+H), 591.33    (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-ethylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #41, ¹H NMR (DMSO-d₆, 300 MHz): ¹H NMR (DMSO-d₆) d: 9.04    (s, 1H), 8.28 (s, 1H), 7.93 (s, 1H), 7.84 (s br, 2H), 7.66-7.75 (m,    1H), 7.40-7.50 (m, 3H), 7.32-7.40 (m, 1H), 7.29 (s, 1H), 7.01 (d,    J=8.3 Hz, 1H), 2.96-3.11 (m, 1H), 2.44-2.82 (m, 13H), 2.06-2.30 (m,    4H), 1.17-1.51 (m, 6H), 0.82 (t, J=7.3 Hz, 6H) ppm; MS (ES) 537.20    (M+H), 535.27 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(but-2-enylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #42, MS (ES) 507.16 (M+H), 505.11 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(butyl(but-2-enyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #43, MS (ES) 562.16 (M);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #44, MS (ES) 554.10 (M+H), 552.22 (M−H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine,    compound #45, ¹H NMR (DMSO-d₆, 300 MHz): 9.23 (s, 1H), 8.54-8.69 (m,    1H), 8.10 (d, 1H), 7.98 (s, 1H), 7.87 (s br, 2H), 7.31-7.56 (m, 3H),    6.97 (t, 1H), 3.38-3.43 (m, 3H), 2.53-2.80 (m, 6H), 2.18-2.41 (m,    5H), 1.97-2.15 (m, 2H), 1.84-1.97 (m, 3H), 1.42-1.76 (m, 4H) ppm; MS    (ES) 541.63 (M+H), 539.45 (M−H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #46, ¹H NMR (DMSO-d₆, 300 MHz) 9.04 (s, 1H), 8.59 (d, 1H),    8.21 (s, 1H), 8.06 (d, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.62-7.43    (m, 2H), 7.26 (s, 1H), 6.95 (d, 1H) 2.92 (m, 1H), 2.68-2.42 (m, 4H),    2.44 (s, 2H), 2.29 (m, 2H), 2.05 (m, 2H), 1.29 (m, 2H), 1.01 (m, 4H)    ppm; MS (ES) 454.37 (M+H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #47, ¹H NMR (DMSO-d₆, 300 MHz) 9.03 (s, 1H), 8.53 (d, 1H),    8.25 (s, 1H), 8.11 (d, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.51-7.39    (m, 2H), 7.26 (s, 1H), 7.08 (d, 1H), 2.92 (m, 1H), 2.72-2.48 (m,    8H), 2.40 (s, 2H), 2.31 (m, 2H), 2.02 (m, 2H), 1.25 (m, 2H), 1.06    (m, 4H) ppm; MS (ES) 482.08 (M+H), 480.23 (M−H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #48, ¹H NMR (DMSO-d₆, 300 MHz) 9.05 (s, 1H), 8.58 (d, 1H),    8.22 (s, 1H), 8.09 (d, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.56-7.38    (m, 2H), 7.28 (s, 1H), 7.03 (d, 1H), 2.98 (m, 1H), 2.79-2.52 (m,    12H), 2.49 (s, 2H), 2.33 (m, 2H), 2.04 (m, 2H), 1.27 (m, 2H), 1.03    (m, 4H) ppm; MS (ES) 510.57 (M+H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #49, ¹H NMR (DMSO-d₆, 300 MHz) 9.04 (s, 1H), 8.58 (d, 1H),    8.18 (s, 1H), 8.08 (d, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.60-7.40    (m, 2H), 7.28 (s, 1H), 6.99 (d, 1H), 2.86-2.56 (m, 10H), 2.41-2.24    (m, 6H), 1.99 (m, 2H), 1.50-1.09 (m, 5H), 0.82 (t, 6H) ppm; MS (ES)    538.15 (M+H), 536.25 (M−H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #50, ¹H NMR (DMSO-d₆, 300 MHz) 9.05 (s, 1H), 8.60 (d, 1H),    8.21 (s, 1H), 8.09 (d, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.55-7.39    (m, 2H), 7.26 (s, 1H), 7.00 (d, 1H), 3.10 (t, 2H), 2.77-2.54 (m,    8H), 2.45-2.22 (m, 6H), 2.01 (m, 4H), 1.30-1.09 (m, 2H), 0.84 (m,    2H), 0.43 (d, 3H), 0.10 (d, 2H) ppm; MS (ES) 562.16 (M+H), 560.39    (M−H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #51, ¹H NMR (DMSO-d₆, 300 MHz) 9.04 (s, 1H), 8.59 (d, 1H),    8.21 (s, 1H), 8.06 (d, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.62-7.43    (m, 2H), 7.26 (s, 1H), 6.95 (d, 1H), 2.83-2.59 (m, 6H), 2.51-2.31    (m, 6H), 2.01 (m, 2H), 1.66-1.38 (m, 5H), 1.24 (m, 6H), 0.88 (d,    6H), 0.83 (d, 6H) ppm; MS (ES) 594.21 (M+H); 592.25 (M−H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #52, ¹H NMR (DMSO-d₆, 300 MHz) 9.04 (s, 1H), 8.59 (d, 1H),    8.29 (s, 1H), 8.10 (d, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.55-7.39    (m, 2H), 7.24 (s, 1H), 6.99 (d, 1H), 2.93-2.53 (m, 8H), 2.31 (m,    4H), 2.11 (m, 2H), 1.96 (m, 2H), 1.80 (m, 2H), 1.62 (m, 2H),    1.32-1.10 (m, 2H) ppm; MS (ES) 508.05 (M+H), 506.13 (M−H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #53, ¹H NMR (DMSO-d₆, 300 MHz) 9.06 (s, 1H), 8.60 (d, 1H),    8.31 (s, 1H), 8.10 (d, 1H), 7.95 (s, 1H), 7.85 (s, 1H), 7.54-7.39    (m, 2H), 7.27 (s, 1H), 6.97 (d, 1H), 2.89-2.58 (m, 8H), 2.52 (m,    2H), 2.36 (m, 2H), 2.09 (m, 2H), 1.87 (m, 2H), 1.70 (m, 2H), 1.56    (m, 2H), 1.36-1.01 (m, 6H) ppm; MS (ES) 536.12 (M+H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((methylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #54 ¹H NMR (DMSO-d₆, 300 MHz) 9.04 (s, 1H), 8.57 (d, 1H),    8.32 (s, 1H), 8.09 (d, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.57-7.38    (m, 2H), 7.22 (s, 1H), 6.96 (d, 1H), 3.18-3.32 (m, 2H), 3.16-3.12    (m, 1H), 2.80-2.64 (m, 4H), 2.66-2.56 (m, 2H), 2.35-2.07 (m, 5H),    1.41-1.08 (m, 2H), 1.15 (d, J=6.3

Hz, 6H) ppm; MS (ES) 496.09 (M+H), 494.12 (M−H);

-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #55, ¹H NMR (DMSO-d₆, 300 MHz) 9.05 (s, 1H), 8.61 (d, 1H),    8.21 (s, 1H), 8.11 (d, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.57-7.39    (m, 2H), 7.29 (s, 1H), 6.96 (d, 1H), 3.36 (m, 2H) 2.81-2.52 (m, 8H),    2.45-2.21 (m, 6H), 2.01 (m, 2H), 1.87-1.44 (m, 4H), 1.29 (m, 2H)    ppm; MS (ES) 522.12 (M+H), 520.31 (M−H); and-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-butylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #56, ¹H NMR (DMSO-d₆, 300 MHz) 9.06 (s, 1H), 8.60 (d, 1H),    8.27 (s, 1H), 8.07 (d, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.59-7.43    (m, 2H), 7.20 (s, 1H), 7.01 (d, 1H), 3.28 (m, 2H), 2.95-2.63 (m,    8H), 2.19 (m, 5H), 1.75 (m, 2H), 1.41-1.11 (m, 2H), 0.95 (t, 3H)    ppm; MS (ES) 510.09 (M+H), 508.38 (M−H).

Biological Example 1 Phospho-Akt In-Cell Western Assay

The compounds of the invention were tested in the following assay fortheir ability to inhibit Axl activity.

Reagents and Buffers:

-   Cell culture plate: 96 well assay plate (Corning 3610), white, clear    bottom, tissue-culture treated.-   Cells: Hela cells.-   Starvation medium: For Axl stimulation: 0.5% FCS (fetal calf serum)    in DMEM, plus Axl/Fc (extracellular domain of AXL fused to    immunoglobulin Fc region) (R&D, 154-AL) 500 ng/mL.-   For EGF (epidermal growth factor) stimulation: 0.5% FCS in DMEM    (Dulbecco's modified Eagles medium).-   Poly-L-Lysine 0.01% solution (the working solution): 10 pg/ml,    dilute In PBS (phosphate buffered saline).-   Axl antibody cross-linking:    -   1^(st): Mouse anti-Axl (R&D, MAB154).    -   2^(nd): Biotin-SP-conjugated AffiniPure goat anti-mouse IgG        (H+L) (Jackson ImmunoResearch #115-065-003).-   Fixing buffer: 4% formaldehyde in PBS.-   Wash buffer: 0.1% TritonX-100 in PBS.-   Quenching buffer: 3% H₂O₂, 0.1% Azide in wash buffer, Azide and    hydrogen peroxide (H₂O₂) are added fresh.-   Blocking buffer: 5% BSA in TBST (tris buffered saline plus 0.1%    Tween 20).-   Primary antibody: Rabbit anti-human Phospho-Akt antibody (Cell    Signaling 9271): 1×250 diluted in blocking buffer.-   Secondary antibody: HRP (horse radish peroxidase)-conjugated Goat    anti-Rabbit secondary, stock solution: Jackson ImmunoResearch (Goat    anti-Rabbit HRP, #111-035-144) 1:1 diluted in glycerol, store at    −20° C. The working solution: 1× 2000 dilution of stock in blocking    buffer.-   Chemiluminescent working solution (Pierce, 37030): SuperSignal ELISA    (enzyme linked immunosorbant assay) Pico Chemiluminescent substrate.-   Crystal Violet solution: Stock: 2.5% Crystal violet in methanol,    filtered and kept at ambient temperature. The working solution:    dilute the stock 1:20 with PBS immediately before use.-   10% SDS: working solution: 5% SDS (sodium dodecylsulfate), diluted    in PBS

Methods: Day 1:

A 96 well TC (tissue culture treated) plate was coated with 10 μg/mLpoly-L-Lysine at 37° C. for 30 min, washed twice with PBS, and air-driedfor 5 minutes before cells were added. Hela cells were seeded at 10,000cells/well and the cells were starved in 100 μL starvation mediumcontaining Axl/Fc for 24 hrs.

Day 2:

The cells were pre-treated with test compounds by adding 100 μL of 2×test compound to the starvation medium on the cells. The cells wereincubated at 37° C. for 1 hr before stimulation.

The cells were stimulated by Axl-antibody cross-linking as follows: A 5×1^(St)/2nd Axl antibody mixture was made (37.5 μg/mL 1^(st)/100 μg/mL2^(nd)) in starvation medium and nutated at 4° C. with thorough mixingfor 1-2 hours for clustering. The resulting mix was warmed to 37° C. 50μL of 5× Axl 1^(st)/2^(nd) of antibody cluster was added to the cellsand the cells were incubated at 37° C. for 5 min. After 5 minutesstimulation, the plate was flicked to remove medium and the plate wastapped onto paper towels. Formaldehyde (4.0% in PBS, 100 μL) was addedto fix the cells and the cells were incubated at ambient temperature for20 min without shaking.

The cells were washed with a plate washer buffer to remove theformaldehyde solution. The plate was flicked to removed excess washbuffer and tapped onto paper towels. Quenching buffer (100 μL) was addedto each well and the cells were incubated at ambient temperature for 20minutes without shaking.

The cells were washed with a plate washer buffer to remove the quenchingbuffer. Blocking buffer (100 μL) was added and the cells were incubatedat ambient temperature for at least an hour with gentle shaking.

The cells were washed with a plate washer buffer and diluted primaryantibody (50 μL) was added to each well (blocking buffer was added tothe negative control wells instead). The plates were incubated overnightat 4° C. with gentle shaking.

Day 3:

The wash buffer was removed, diluted secondary antibody (100 μL) wasadded, and the cells were incubated at ambient temperature for 1 hourwith gentle shaking. During the incubation, the chemiluminescent reagentwas brought to ambient temperature.

The secondary antibody was removed by washing the cells 1× with washbuffer, 1× with PBS by plate washer. The PBS was removed from the plateand the chemiluminescent reagent (80 μL: 40 μL A and 40 μL B) was addedto each well at ambient temperature.

The resulting chemiluminescence was read with a Luminomitor within 10minutes to minimize changes in signal intensity. After reading thechemiluminescence, the cells were washed 1× with wash buffer and 1× withPBS by plate washer. The plate was tapped onto paper towels to removeexcess liquid from wells and air-dried at ambient temperature for 5minutes.

Crystal Violet working solution (60 μL) was added to each well and thecells were incubated at ambient temperature for 30 min. The crystalviolet solution was removed, and the wells were rinsed with PBS, thenwashed 3× with PBS (200 μL) for 5 minutes each.

5% SDS solution (70 μL) was added to each well and the cells wereincubated on a shaker for 30 min at ambient temperature.

The absorbance was read at 590 nM on a Wallac photospec. The 590 nMreadings indicated the relative cell number in each well. This relativecell number was then used to normalize each luminescence reading.

The results of the ability of the compounds of the invention to inhibitAxl activity, when tested in the above assay, are shown in the followingTables wherein the level of activity (i.e., the IC₅₀) for each compoundis indicated in each Table. The compound numbers in the Tables referredto the compounds disclosed herein as being prepared by the methodsdisclosed herein:

TABLE 1 (Ia)

Cpd # Compound Name A R¹ IC₅₀ 11-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(acetamido)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 2 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(methoxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 3 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4,4-difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

B 4 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 5 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 6 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 7 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 8 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((carboxymethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

B 9 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 10 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

B 11 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

D 13 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

D 15 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

B 16 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7s)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 17 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-methylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 18 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((propyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 19 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 20 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 21 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 22 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 23 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((1-cyclopentylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

B 24 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((methylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 25 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((3,3-dimethylbut-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

B 26 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 27 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

C 28 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((5-chlorothien-2-yl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

B 29 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-carboxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

B 30 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((3-bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

B 31 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 32 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 33 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-pentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 34 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2,2-dimethylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 35 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

B 36 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 37 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine═C(H)—

B 38 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine═C(H)—

A 39 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-methylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 40 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

B 41 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-ethylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 42 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(but-2-enylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 43 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(butyl(but-2-enyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═C(H)—

A 441-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═N—

D 46 1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═N—

A 47 1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═N—

B 48 1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═N—

A 49 1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═N—

A 50 1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═N—

A 51 1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═N—

B 52 1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═N—

A 53 1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═N—

A 54 1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((methylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═N—

A 55 1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═N—

NA 56 1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-butylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine ═N—

NA IC₅₀ activity: A = <1 μM B = 1 to 10 μM C = >10 to 20 μM D = >20 μM

TABLE 2 (Ib)

Cpd # Compound Name A R¹ IC₅₀ 12 1-(6,7-dihydro- 5H-benzo[6,7]cyclohepta[1,2-c] pyridazin-3- yl)-N⁵-(7- (pyrrolidin-1-yl)-6,7,8,9-tetrahydro- 5H-benzo [7]annulene-1- yl)-1H-1,2,4-triazole-3,5-diamine ═CH—

A 14 1-(6,7-dihydro- 5H-benzo[6,7] cyclohepta[1,2-c] pyridazin-3-yl)-N⁵- ((7S)-7-(t- butoxycarbonylamino)- 6,7,8,9-tetrahydro-5H-benzo[7]annulene- 2-yl)-1H-1,2,4- triazole-3,5-diamine ═CH—

D IC₅₀ activity: A = <1 μM B = 1 to 10 μM C = >10 to 20 μM D = >20 μM

TABLE 3 (II)

Cpd # Compound Name A R^(2c) R^(2d) IC₅₀ 451-(6,7-dihydro-5H-pyrido[2′,3′:6,7] cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4- (pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4- triazole-3,5-diamine ═N—

—F D IC₅₀ activity: A = <1 μM B = 1 to 10 μM C = >10 to 20 μM D = >20 μM

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification and/or listedin the Application Data Sheet are incorporated herein by reference, intheir entireties.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

1. A compound of formula (I):

wherein: A is ═C(H)— or ═N—; R¹ is —N(R²)R³, —N(R²)C(O)R³ or—N(R²)—R⁴—C(O)OR³; or R¹ is an N-heterocyclyl optionally substituted byone or more substituents selected from the group consisting of halo and—R⁴—C(O)OR²; each R² and R³ is hydrogen, alkyl, alkenyl, optionallysubstituted aralkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl and optionally substituted heteroarylalkyl;and each R⁴ is independently selected from the group consisting of adirect bond and an optionally substituted straight or branched alkylenechain; as an isolated stereoisomer or mixture thereof, or apharmaceutically acceptable salt thereof; provided that the compound offormula (I) is not a compound selected from the group consisting of:1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((bicyclo[2.2.1]heptan-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((bicyclo[2.2.1]heptan-2-yl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;and1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-diethylamino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.2. The compound of claim 1 wherein the compound of formula (I) is acompound of formula (Ia):

wherein: A is ═C(H)— or ═N—; R¹ is —N(R²)R³, —N(R²)C(O)R³ or—N(R²)—R⁴—C(O)OR³; or R¹ is an N-heterocyclyl optionally substituted byone or more substituents selected from the group consisting of halo and—R⁴—C(O)OR²; each R² and R³ is independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl and optionally substituted heteroarylalkyl; and each R⁴is independently selected from the group consisting of a direct bond andan optionally substituted straight or branched alkylene chain.
 3. Thecompound of claim 2 wherein: A is ═C(H)—; R¹ is —N(R²)R³, —N(R²)C(O)R³or —N(R²)—R⁴—C(O)OR³; or R¹ is an N-heterocyclyl optionally substitutedby one or more substituents selected from the group consisting of haloand —R⁴—C(O)OR²; each R² and R³ is independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl and optionally substituted heteroarylalkyl; and each R⁴is independently selected from the group consisting of a direct bond andan optionally substituted straight or branched alkylene chain.
 4. Thecompound of claim 3 wherein: A is ═C(H)—; R¹ is —N(R²)R³; and R² and R³are each independently selected from the group consisting of hydrogen,alkyl, alkenyl, optionally substituted aralkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl and optionallysubstituted heteroarylalkyl.
 5. The compound of claim 4 having thefollowing formula (Ia1):

wherein: R² and R³ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl and optionally substituted heteroarylalkyl.
 6. Thecompound of claim 5 wherein R² and R³ are each independently selectedfrom the group consisting of hydrogen, alkyl and alkenyl.
 7. Thecompound of claim 5 wherein R² and R³ are each independently selectedfrom the group consisting of hydrogen, optionally substituted cycloalkyland optionally substituted cycloalkylalkyl.
 8. The compound of claim 5wherein R² and R³ are each independently selected from the groupconsisting of hydrogen, optionally substituted aralkyl and optionallysubstituted heteroarylalkyl.
 9. The compound of claim 3 wherein: A is═C(H)—; R¹ is —N(R²)C(O)R³; and R² and R³ are each independentlyselected from the group consisting of hydrogen, alkyl, alkenyl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl and optionally substitutedheteroarylalkyl.
 10. The compound of claim 9 having the followingformula (Ia2):

wherein R² and R³ are each independently selected from the groupconsisting of hydrogen and alkyl.
 11. The compound of claim 3 wherein: Ais ═C(H)—; R¹ is —N(R²)—R⁴—C(O)OR³; R² and R³ are each independentlyselected from the group consisting of hydrogen, alkyl, alkenyl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl and optionally substitutedheteroarylalkyl; and R⁴ is selected from the group consisting of adirect bond and an optionally substituted straight or branched alkylenechain.
 12. The compound of claim 11 having the following formula (Ia3):

wherein: R² and R³ are each independently selected from the groupconsisting of hydrogen and alkyl; and R⁴ is selected from the groupconsisting of a direct bond and a methylene chain.
 13. The compound ofclaim 3 wherein: A is ═C(H)—; R¹ is an N-heterocyclyl optionallysubstituted by one or more substituents selected from the groupconsisting of halo and —R⁴—C(O)OR²; and R² is selected from the groupconsisting of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl and optionally substituted heteroarylalkyl.
 14. Thecompound of claim 13 wherein: A is ═C(H)—; R¹ is pyrrolidinyl,piperidinyl or piperazinyl, each independently optionally substituted byone or more substituents selected from the group consisting of halo and—R⁴—C(O)OR²; and R² is selected from the group consisting of hydrogenand alkyl.
 15. The compound of claim 2 wherein: A is ═N—; R¹ is—N(R²)R³, —N(R²)C(O)R³ or —N(R²)—R⁴—C(O)OR³; or R¹ is an N-heterocyclyloptionally substituted by one or more substituents selected from thegroup consisting of halo and —R⁴—C(O)OR²; each R² and R³ isindependently selected from the group consisting of hydrogen, alkyl,alkenyl, optionally substituted aralkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl and optionallysubstituted heteroarylalkyl; and each R⁴ is independently selected fromthe group consisting of a direct bond and an optionally substitutedstraight or branched alkylene chain.
 16. The compound of claim 15wherein: A is ═N—; R¹ is —N(R²)—R⁴—C(O)OR³, each R² and R³ isindependently selected from the group consisting of hydrogen, alkyl,alkenyl, optionally substituted aralkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl and optionallysubstituted heteroarylalkyl; and each R⁴ is independently selected fromthe group consisting of a direct bond or an optionally substitutedstraight or branched alkylene chain.
 17. The compound of claim 16 havingthe following formula (Ia4):

wherein: R² and R³ are each independently selected from the groupconsisting of hydrogen and alkyl; and R⁴ is a direct bond or a methylenechain.
 18. The compound of claim 15 having the following formula (Ia5):

wherein: R² and R³ are each independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl and cycloalkylalkyl.
 19. Thecompound of claim 1 wherein the compound of formula (I) is a compound offormula (Ib):

wherein: A is ═C(H)— or ═N—; R¹ is —N(R²)R³, —N(R²)C(O)R³ or—N(R²)—R⁴—C(O)OR³; or R¹ is an N-heterocyclyl optionally substituted byone or more substituents selected from the group consisting of halo and—R⁴—C(O)OR²; each R² and R³ is independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl and optionally substituted heteroarylalkyl; and each R⁴is independently selected from the group consisting of a direct bond andan optionally substituted straight or branched alkylene chain; and as anisolated stereoisomer or mixture thereof, or a pharmaceuticallyacceptable salt thereof.
 20. The compound of claim 19 wherein: A is═C(H)—; R¹ is —N(R²)R³, —N(R²)C(O)R³ or —N(R²)—R⁴—C(O)OR³; or R¹ is anN-heterocyclyl optionally substituted by one or more substituentsselected from the group consisting of halo and —R⁴—C(O)OR²; each R² andR³ is independently selected from the group consisting of hydrogen,alkyl, alkenyl, optionally substituted aralkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl and optionallysubstituted heteroarylalkyl; and each R⁴ is independently selected fromthe group consisting of a direct bond and an optionally substitutedstraight or branched alkylene chain.
 21. The compound of claim 20wherein: A is ═C(H)—; R¹ is —N(R²)—R⁴—C(O)OR³; R² and R³ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, optionally substituted aralkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl and optionallysubstituted heteroarylalkyl; and R⁴ is selected from the groupconsisting of a direct bond and an optionally substituted straight orbranched alkylene chain.
 22. The compound of claim 20 having thefollowing formula (Ib1):

wherein: R² and R³ are each independently selected from the groupconsisting of hydrogen and alkyl; and R⁴ is selected from the groupconsisting of a direct bond and a methylene chain.
 23. The compound ofclaim 20 wherein: A is ═C(H)—; R¹ is an N-heterocyclyl optionallysubstituted by one or more substituents selected from the groupconsisting of halo and —R⁴—C(O)OR²; and R² is selected from the groupconsisting of hydrogen, alkyl, alkenyl, optionally substituted aralkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl and optionally substituted heteroarylalkyl.
 24. Thecompound of claim 23 wherein: A is ═C(H)—; R¹ is pyrrolidinyl optionallysubstituted by one or more substituents selected from the groupconsisting of halo and —R⁴—C(O)OR²; and R² is selected from the groupconsisting of hydrogen and alkyl.
 25. A compound of formula (II):

wherein: R⁵ is N-heterocyclyl optionally substituted by N-heterocyclyl;and R⁶ is halo; as an isolated stereoisomer or mixture thereof, or apharmaceutically acceptable salt thereof.
 26. The compound of claim 25wherein: R⁵ is piperidinyl substituted by pyrrolidinyl; and R⁶ is halo.27. The compound of claim 1 or claim 26 selected from the groupconsisting of:1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-methylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((propyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-propylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-0)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((3,3-dimethylbut-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-pentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2,2-dimethylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-methylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-ethylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(but-2-enylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(butyl(but-2-enyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7s)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((1-cyclopentylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((5-chlorothien-2-yl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-carboxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((3-bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(acetamido)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((carboxymethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(methoxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4,4-difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′.:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((methylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-butylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine;and1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine.28. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a therapeutically effective amount of acompound of any one of claims 1 to 27, as an isolated stereoisomer ormixture thereof, or a pharmaceutically acceptable salt thereof.
 29. Amethod of treating a disease or condition associated with Axl activityin a mammal, wherein the method comprises administering to the mammal atherapeutically effective amount of a compound of any one of claims 1 to27, as an isolated stereoisomer or mixture thereof, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of claim
 28. 30. A method of preparing an (S)-enantiomer ofthe following formula:

where n and m are the same and are 0, 1 or 2; R⁷ is nitro, halo or—C(O)OR²; and R² is hydrogen, alkyl, alkenyl, optionally substitutedaralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl and optionally substituted heteroaryl; wherein themethod comprises treating a compound of formula (I):

where n and m are the same and are 0, 1 or 2; R⁷ is nitro, halo or—C(O)OR²; and R² is hydrogen, alkyl, alkenyl, optionally substitutedaralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl and optionally substituted heteroaryl; with an aminodonor molecule in the presence of a catalytic amount of a (S)-specifictransaminase under suitable conditions to form the (S)-enantiomer.